Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data

References

• Ali SN, Dayarathna TK, Ali AN, Osumah T, Ahmed M, Cooper TT, Power NE, Zhang D, Kim D, Kim R, et al. 2018. Drosophila melanogaster as a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients. Dis Models Mech. 11(11):dmm03587.
   Web of Science ®Google Scholar
• Aliwarga T, Evangelista EA, Sotoodehnia N, Lemaitre RN, Totah RA. 2018. Regulation of CYP2J2 and EET levels in cardiac disease and diabetes. Int J Mol Sci. 19(7):1916.
   PubMed Web of Science ®Google Scholar
• Alkharfy KM, Ali FA, Alkharfy MA, Jan BL, Raish M, Alqahtani S, Ahmad A. 2020. Effect of compromised liver function and acute kidney injury on the pharmacokinetics of thymoquinone in a rat model. Xenobiotica. 50(7):858–862.
   PubMed Web of Science ®Google Scholar
• Almeida AR, Alves M, Domingues I, Henriques I. 2019. The impact of antibiotic exposure in water and zebrafish gut microbiomes: a 16S rRNA gene-based metagenomic analysis. Ecotoxicol Environ Saf. 186:109771.
   PubMed Web of Science ®Google Scholar
• Amore BM, Gibbs JP, Emery MG. 2010. Application of in vivo animal models to characterize the pharmacokinetic and pharmacodynamic properties of drug candidates in discovery settings. Comb Chem High Throughput Screen. 13(2):207–218.
   PubMed Web of Science ®Google Scholar
• Anderson S, Luffer-Atlas D, Knadler MP. 2009. Predicting circulating human metabolites: how good are we? Chem Res Toxicol. 22(2):243–256.
   PubMed Web of Science ®Google Scholar
• Apfeld J, Alper S. 2018. What can we learn about human disease from the nematode C. elegans? Methods Mol Biol. 1706:53–75.
   PubMedGoogle Scholar
• Apte U. 2014. Galactosamine. In: Wexler P, editor. Encyclopedia of toxicology. 3rd ed. Oxford (UK): Academic Press; p. 689–690.
   Google Scholar
• Arora T, Mehta AK, Joshi V, Mehta KD, Rathor N, Mediratta PK, Sharma KK. 2011. Substitute of animals in drug research: an approach towards fulfillment of 4R’s. Indian J Pharm Sci. 73(1):1–6.
   PubMed Web of Science ®Google Scholar
• Askari A, Thomson SJ, Edin ML, Zeldin DC, Bishop-Bailey D. 2013. Roles of the epoxygenase CYP2J2 in the endothelium. Prostaglandins Other Lipid Mediat. 107:56–63.
   PubMed Web of Science ®Google Scholar
• Austin RP, Barton P, Mohmed S, Riley RJ. 2005. The binding of drugs to hepatocytes and its relationship to physicochemical properties. Drug Metab Dispos. 33(3):419–425.
   PubMed Web of Science ®Google Scholar
• Badée J, Achour B, Rostami-Hodjegan A, Galetin A. 2015. Meta-analysis of expression of hepatic organic anion–transporting polypeptide (OATP) transporters in cellular systems relative to human liver tissue. Drug Metab Dispos. 43(4):424–432.
   PubMed Web of Science ®Google Scholar
• Bai JP, Bell R, Buckman S, Burckart GJ, Eichler H-G, Fang KC, Goodsaid FM, Jusko WJ, Lesko LL, Meibohm B. 2011. Translational biomarkers: from preclinical to clinical a report of 2009 AAPS/ACCP Biomarker Workshop. Amsterdam (The Netherlands): Springer.
   Google Scholar
• Barter ZE, Bayliss MK, Beaune PH, Boobis AR, Carlile DJ, Edwards RJ, Houston JB, Lake BG, Lipscomb JC, Pelkonen OR, et al. 2007. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human micro-somal protein and hepatocellularity per gram of liver. Curr Drug Metab. 8(1):33–45.
   PubMed Web of Science ®Google Scholar
• Bell CC, Dankers ACA, Lauschke VM, Sison-Young R, Jenkins R, Rowe C, Goldring CE, Park K, Regan SL, Walker T, et al. 2018. Comparison of hepatic 2D sandwich cultures and 3D spheroids for long-term toxicity applications: a multicenter study. Toxicol Sci. 162(2):655–666.
   PubMed Web of Science ®Google Scholar
• Bell CC, Hendriks DFG, Moro SML, Ellis E, Walsh J, Renblom A, Fredriksson Puigvert L, Dankers ACA, Jacobs F, Snoeys J, et al. 2016. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci Rep. 6(1):25187–25113.
   PubMed Web of Science ®Google Scholar
• Bell CC, Lauschke VM, Vorrink SU, Palmgren H, Duffin R, Andersson TB, Ingelman-Sundberg M. 2017. Transcriptional, functional, and mechanistic comparisons of stem cell–derived hepatocytes, HepaRG cells, and three-dimensional human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury. Drug Metab Dispos. 45(4):419–429.
   PubMed Web of Science ®Google Scholar
• Benet LZ, Bowman CM, Liu S, Sodhi JK. 2018. The extended clearance concept following oral and intravenous dosing: theory and critical analyses. Pharm Res. 35(12):1–12.
   Web of Science ®Google Scholar
• Benet LZ, Bowman CM, Sodhi JK. 2019. How transporters have changed basic pharmacokinetic understanding. AAPS J. 21(6):1–6.
   Web of Science ®Google Scholar
• Benet LZ, Sodhi JK. 2020. Investigating the theoretical basis for in vitro–in vivo extrapolation (ivive) in predicting drug metabolic clearance and proposing future experimental pathways. AAPS J. 22(5):1–11.
   Web of Science ®Google Scholar
• Berezhkovskiy LM. 2011. The corrected traditional equations for calculation of hepatic clearance that account for the difference in drug ionization in extracellular and intracellular tissue water and the corresponding corrected PBPK equation. J Pharm Sci. 100(3):1167–1183.
   PubMed Web of Science ®Google Scholar
• Berghmans S, Butler P, Goldsmith P, Waldron G, Gardner I, Golder Z, Richards FM, Kimber G, Roach A, Alderton W, et al. 2008. Zebrafish based assays for the assessment of cardiac, visual and gut function – potential safety screens for early drug discovery. J Pharmacol Toxicol Methods. 58(1):59–68.
   PubMedGoogle Scholar
• Bertotto LB, Catron TR, Tal T. 2020. Exploring interactions between xenobiotics, microbiota, and neurotoxicity in zebrafish. Neurotoxicology. 76:235–244.
   PubMed Web of Science ®Google Scholar
• Bhutani P, Joshi G, Raja N, Bachhav N, Rajanna PK, Bhutani H, Paul AT, Kumar R. 2021. US FDA approved drugs from 2015–June 2020: a perspective. J Med Chem. 64(5):2339–2381.
   PubMed Web of Science ®Google Scholar
• Bi Y-a, Ryu S, Tess DA, Rodrigues AD, Varma MVS. 2021. Effect of human plasma on hepatic uptake of organic anion. Drug Metab Dispos. 49(1):72–83.
   PubMed Web of Science ®Google Scholar
• Blanchard N, Hewitt NJ, Silber P, Jones H, Coassolo P, Lavé T. 2006. Prediction of hepatic clearance using cryopreserved human hepatocytes: a comparison of serum and serum‐free incubations. J Pharm Pharmacol. 58(5):633–641.
   PubMed Web of Science ®Google Scholar
• Blanchard N, Richert L, Notter B, Delobel F, David P, Coassolo P, Lavé T. 2004. Impact of serum on clearance predictions obtained from suspensions and primary cultures of rat hepatocytes. Eur J Pharm Sci. 23(2):189–199.
   PubMed Web of Science ®Google Scholar
• Bogaards JJ, Bertrand M, Jackson P, Oudshoorn MJ, Weaver RJ, van Bladeren PJ, Walther B. 2000. Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica. 30(12):1131–1152.
   PubMed Web of Science ®Google Scholar
• Bonn B, Svanberg P, Janefeldt A, Hultman I, Grime K. 2016. Determination of human hepatocyte intrinsic clearance for slowly metabolized compounds: comparison of a primary hepatocyte/stromal cell co-culture with plated primary hepatocytes and HepaRG. Drug Metab Dispos. 44(4):527–533.
   PubMed Web of Science ®Google Scholar
• Bowman C, Benet L. 2018. An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation. Eur J Pharm Sci. 123:502–514.
   PubMed Web of Science ®Google Scholar
• Bowman CM, Benet LZ. 2016. Hepatic clearance predictions from in vitro–in vivo extrapolation and the biopharmaceutics drug disposition classification system. Drug Metab Dispos. 44(11):1731–1735.
   PubMed Web of Science ®Google Scholar
• Bowman CM, Chen E, Chen L, Chen Y-C, Liang X, Wright M, Chen Y, Mao J. 2020. Changes in organic anion transporting polypeptide uptake in HEK293 overexpressing cells in the presence and absence of human plasma. Drug Metab Dispos. 48(1):18–24.
   PubMed Web of Science ®Google Scholar
• Bowman CM, Okochi H, Benet LZ. 2019. The presence of a transporter-induced protein binding shift: a new explanation for protein-facilitated uptake and improvement for in vitro-in vivo extrapolation. Drug Metab Dispos. 47(4):358–363.
   PubMed Web of Science ®Google Scholar
• Boyd WA, McBride SJ, Rice JR, Snyder DW, Freedman JH. 2010. A high-throughput method for assessing chemical toxicity using a Caenorhabditis elegans reproduction assay. Toxicol Appl Pharmacol. 245(2):153–159.
   PubMed Web of Science ®Google Scholar
• Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCast™ Phase I and Phase II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect. 124(5):586–593.
   PubMed Web of Science ®Google Scholar
• Brown HS, Griffin M, Houston JB. 2007. Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metab Dispos. 35(2):293–301.
   PubMed Web of Science ®Google Scholar
• Bteich M, Poulin P, Haddad S. 2019. The potential protein-mediated hepatic uptake: discussion on the molecular interactions between albumin and the hepatocyte cell surface and their implications for the in vitro-to-in vivo extrapolations of hepatic clearance of drugs. Expert Opin Drug Metab Toxicol. 15(8):633–658.
   PubMed Web of Science ®Google Scholar
• Cantrill C, Houston JB. 2017. Understanding the interplay between uptake and efflux transporters within in vitro systems in defining hepatocellular drug concentrations. J Pharm Sci. 106(9):2815–2825.
   PubMed Web of Science ®Google Scholar
• Carlessi R, Köhn-Gaone J, Olynyk JK, et al. Mouse Models of Hepatocellular Carcinoma. In: Tirnitz-Parker JEE, editor. Hepatocellular Carcinoma [Internet]. Brisbane (AU): Codon Publications; 2019 Oct 24. Chapter 4. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549197/
   Google Scholar
• Cerny MA. 2016. Prevalence of non–cytochrome P450–mediated metabolism in Food and Drug Administration–approved oral and intravenous drugs: 2006–2015. Drug Metab Dispos. 44(8):1246–1252.
   PubMed Web of Science ®Google Scholar
• Chan TS, Yu H, Moore A, Khetani SR, Tweedie D. 2013. Meeting the challenge of predicting hepatic clearance of compounds slowly metabolized by cytochrome P450 using a novel hepatocyte model, HepatoPac. Drug Metab Dispos. 41(12):2024–2032.
   PubMed Web of Science ®Google Scholar
• Chan TS, Yu H, Moore A, Khetani SR, Tweedie D. 2019. Meeting the challenge of predicting hepatic clearance of compounds slowly metabolized by cytochrome P450 using a novel hepatocyte model, HepatoPac. Drug Metab Dispos. 47(1):58–66.
   PubMed Web of Science ®Google Scholar
• Chen Z, Zhijie C, Yuting Z, Shilin X, Qichun Z, Jinying O, Chaohua L, Jing L, Zhixian M. 2020. Antibiotic-driven gut microbiome disorder alters the effects of sinomenine on morphine-dependent zebrafish. Front Microbiol. 11:946.
   PubMed Web of Science ®Google Scholar
• Chiba M, Ishii Y, Sugiyama Y. 2009. Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J. 11(2):262–276.
   PubMed Web of Science ®Google Scholar
• Chng HT, Ho HK, Yap CW, Lam SH, Chan EC. 2012. An investigation of the bioactivation potential and metabolism profile of zebrafish versus human. J Biomol Screen. 17(7):974–986.
   PubMedGoogle Scholar
• Cho HJ, Kim JE, Kim DD, Yoon IS. 2014. In vitro-in vivo extrapolation (IVIVE) for predicting human intestinal absorption and first-pass elimination of drugs: principles and applications. Drug Dev Ind Pharm. 40(8):989–998.
   PubMed Web of Science ®Google Scholar
• Choi GW, Lee YB, Cho HY. 2019. Interpretation of non-clinical data for prediction of human pharmacokinetic parameters: in vitro-in vivo extrapolation and allometric scaling. Pharmaceutics. 11(4):168.
   PubMed Web of Science ®Google Scholar
• Chothe PP, Wu S-P, Ye Z, Hariparsad N. 2018. Assessment of transporter-mediated and passive hepatic uptake clearance using rifamycin-SV as a pan-inhibitor of active uptake. Mol Pharm. 15(10):4677–4688.
   PubMed Web of Science ®Google Scholar
• Chu X, Bleasby K, Evers R. 2013. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol. 9(3):237–252.
   PubMed Web of Science ®Google Scholar
• Chu X, Korzekwa K, Elsby R, Fenner K, Galetin A, Lai Y, Matsson P, Moss A, Nagar S, Rosania GR. et al. 2013. Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Clin Pharmacol Ther. 94(1):126–141.
   PubMed Web of Science ®Google Scholar
• Chung H, Sztal T, Pasricha S, Sridhar M, Batterham P, Daborn PJ. 2009. Characterization of Drosophila melanogaster cytochrome P450 genes. Proc Natl Acad Sci. 106(14):5731–5736.
   PubMed Web of Science ®Google Scholar
• Cohen A. 2008. Pharmacokinetic and pharmacodynamic data to be derived from early-phase drug development. Clin Pharmacokinet. 47(6):373–381.
   PubMed Web of Science ®Google Scholar
• Couzin-Frankel J. 2013. When mice mislead. Science. 342(6161):922–923, 925.
   PubMed Web of Science ®Google Scholar
• Da-Silva F, Boulenc X, Vermet H, Compigne P, Gerbal-Chaloin S, Daujat-Chavanieu M, Klieber S, Poulin P. 2018. Improving prediction of metabolic clearance using quantitative extrapolation of results obtained from human hepatic micropatterned cocultures model and by considering the impact of albumin binding. J Pharm Sci. 107(7):1957–1972.
   PubMed Web of Science ®Google Scholar
• Dalvie D, Obach RS, Kang P, Prakash C, Loi C-M, Hurst S, Nedderman A, Goulet L, Smith E, Bu H-Z, et al. 2009. Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem Res Toxicol. 22(2):357–368.
   PubMed Web of Science ®Google Scholar
• Dash A, Inman W, Hoffmaster K, Sevidal S, Kelly J, Obach RS, Griffith LG, Tannenbaum SR. 2009. Liver tissue engineering in the evaluation of drug safety. Expert Opin Drug Metab Toxicol. 5(10):1159–1174.
   PubMed Web of Science ®Google Scholar
• Davies B, Morris T. 1993. Physiological parameters in laboratory animals and humans. Pharm Res. 10(7):1093–1095.
   PubMed Web of Science ®Google Scholar
• De Bruyn T, Augustijns PF, Annaert PP. 2016. Hepatic clearance prediction of nine human immunodeficiency virus protease inhibitors in rat. J Pharm Sci. 105(2):846–853.
   PubMed Web of Science ®Google Scholar
• De Bruyn T, Ufuk A, Cantrill C, Kosa RE, Bi Y-A, Niosi M, Modi S, Rodrigues AD, Tremaine LM, Varma MVS, et al. 2018. Predicting human clearance of organic anion transporting polypeptide substrates using cynomolgus monkey: in vitro–in vivo scaling of hepatic uptake clearance. Drug Metab Dispos. 46(7):989–1000.
   PubMed Web of Science ®Google Scholar
• Di L, Obach RS. 2015. Addressing the challenges of low clearance in drug research. AAPS J. 17(2):352–357.
   PubMed Web of Science ®Google Scholar
• Di L, Trapa P, Obach RS, Atkinson K, Bi Y-A, Wolford AC, Tan B, McDonald TS, Lai Y, Tremaine LM. 2012. A novel relay method for determining low-clearance values. Drug Metab Dispos. 40(9):1860–1865.
   PubMed Web of Science ®Google Scholar
• Dimov I, Maduro MF. 2019. The C. elegans intestine: organogenesis, digestion, and physiology. Cell Tissue Res. 377(3):383–396.
   PubMed Web of Science ®Google Scholar
• Dirksen P, Assié A, Zimmermann J, Zhang F, Tietje A-M, Marsh SA, Félix M-A, Shapira M, Kaleta C, Schulenburg H. 2020. CeMbio-the Caenorhabditis elegans microbiome resource. G3: Genes, Genomes, Genetics. 10(9):3025–3039.
   Web of Science ®Google Scholar
• Docci L, Klammers F, Ekiciler A, Molitor B, Umehara K, Walter I, Krähenbühl S, Parrott N, Fowler S. 2020. In vitro to in vivo extrapolation of metabolic clearance for UGT substrates using short-term suspension and long-term co-cultured human hepatocytes. AAPS J. 22(6):1–12.
   Web of Science ®Google Scholar
• Docci L, Parrott N, Krähenbühl S, Fowler S. 2019. Application of new cellular and microphysiological systems to drug metabolism optimization and their positioning respective to in silico tools. SLAS Discov. 24(5):523–536.
   PubMed Web of Science ®Google Scholar
• Doerksen MJ, Jones RS, Coughtrie MW, Collier AC. 2021. Parameterization of microsomal and cytosolic scaling factors: methodological and biological considerations for scalar derivation and validation. Eur J Drug Metab Pharmacokinet. 46(2):173–111.
   PubMed Web of Science ®Google Scholar
• Douglas AE. 2018. Drosophila and its gut microbes: a model for drug-microbiome interactions. Drug Discov Today Dis Models. 28:43–49.
   PubMedGoogle Scholar
• Ermolaeva MA, Schumacher B. 2014. Insights from the worm: the C. elegans model for innate immunity. Semin Immunol. 26(4):303–309.
   PubMed Web of Science ®Google Scholar
• Fang X, Du Z, Duan C, Zhan S, Wang T, Zhu M, Shi J, Meng J, Zhang X, Yang M, et al. 2021. Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci. 270:118966.
   PubMed Web of Science ®Google Scholar
• Felmlee MA, Morris ME, Mager DE. 2012. Mechanism-based pharmacodynamic modeling. Methods Mol Biol. 929:583–600.
   PubMedGoogle Scholar
• Floby E, Johansson J, Hoogstraate J, Hewitt N, Hill J, Sohlenius-Sternbeck A-K. 2009. Comparison of intrinsic metabolic clearance in fresh and cryopreserved human hepatocytes. Xenobiotica. 39(9):656–662.
   PubMed Web of Science ®Google Scholar
• Fontaine P, Choe K. 2018. The transcription factor SKN-1 and detoxification gene ugt-22 alter albendazole efficacy in Caenorhabditis elegans. Int J Parasitol Drugs Drug Resist. 8(2):312–319.
   PubMed Web of Science ®Google Scholar
• Forker E, Luxon B. 1981. Albumin helps mediate removal of taurocholate by rat liver. J Clin Invest. 67(5):1517–1522.
   PubMed Web of Science ®Google Scholar
• Francis LJ, Houston B, Hallifax D. 2021. Impact of plasma protein binding in drug clearance prediction: a database analysis of published studies and implications for in vitro in vivo extrapolation. Drug Metab Dispos. 49(3):188–201.
   PubMed Web of Science ®Google Scholar
• Frederiksen T, Areberg J, Schmidt E, Bjerregaard Stage T, Brøsen K. 2021. Quantification of in vivo metabolic activity of CYP2D6 genotypes and alleles through population pharmacokinetic analysis of vortioxetine. Clin Pharmacol Ther. 109(1):150–159.
   PubMed Web of Science ®Google Scholar
• Freires IA, Sardi JCO, de Castro RD, Rosalen PL. 2017. Alternative animal and non-animal models for drug discovery and development: bonus or burden? Pharm Res. 34(4):681–686.
   PubMed Web of Science ®Google Scholar
• Fukuchi Y, Toshimoto K, Mori T, Kakimoto K, Tobe Y, Sawada T, Asaumi R, Iwata T, Hashimoto Y, Nunoya K-I, et al. 2017. Analysis of nonlinear pharmacokinetics of a highly albumin-bound compound: contribution of albumin-mediated hepatic uptake mechanism. J Pharm Sci. 106(9):2704–2714.
   PubMed Web of Science ®Google Scholar
• Gabrielsson J, Dolgos H, Gillberg P-G, Bredberg U, Benthem B, Duker G. 2009. Early integration of pharmacokinetic and dynamic reasoning is essential for optimal development of lead compounds: strategic considerations. Drug Discov Today. 14(7–8):358–372.
   PubMed Web of Science ®Google Scholar
• Gabrielsson J, Green AR. 2009. Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. J Pharmacol Exp Ther. 331(3):767–774.
   PubMed Web of Science ®Google Scholar
• Gabrielsson J, Green AR, Van der Graaf PH. 2010. Optimising in vivo pharmacology studies – Practical PKPD considerations. J Pharmacol Toxicol Methods. 61(2):146–156.
   PubMed Web of Science ®Google Scholar
• Gaulke CA, Barton CL, Proffitt S, Tanguay RL, Sharpton TJ. 2016. Triclosan exposure is associated with rapid restructuring of the microbiome in adult zebrafish. PLoS One. 11(5):e0154632.
   PubMed Web of Science ®Google Scholar
• Gill KL, Houston JB, Galetin A. 2012. Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin. Drug Metab Dispos. 40(4):825–835.
   PubMed Web of Science ®Google Scholar
• Goldstone JV, McArthur AG, Kubota A, Zanette J, Parente T, Jönsson ME, Nelson DR, Stegeman JJ. 2010. Identification and developmental expression of the full complement of cytochrome P450 genes in zebrafish. BMC Genomics. 11(1):643.
   PubMed Web of Science ®Google Scholar
• Gould SE, Junttila MR, de Sauvage FJ. 2015. Translational value of mouse models in oncology drug development. Nat Med. 21(5):431–439.
   PubMed Web of Science ®Google Scholar
• Griffin SJ, Houston JB. 2005. Prediction of in vitro intrinsic clearance from hepatocytes: comparison of suspensions and monolayer cultures. Drug Metab Dispos. 33(1):115–120.
   PubMed Web of Science ®Google Scholar
• Grime KH, Barton P, McGinnity DF. 2013. Application of in silico, in vitro and preclinical pharmacokinetic data for the effective and efficient prediction of human pharmacokinetics. Mol Pharm. 10(4):1191–1206.
   PubMed Web of Science ®Google Scholar
• Gutierrez E, Wiggins D, Fielding B, Gould AP. 2007. Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature. 445(7125):275–280.
   PubMed Web of Science ®Google Scholar
• Hackam DG. 2007. Translating animal research into clinical benefit. BMJ. 334(7586):163–164.
   PubMed Web of Science ®Google Scholar
• Hakooz N, Ito K, Rawden H, Gill H, Lemmers L, Boobis AR, Edwards RJ, Carlile DJ, Lake BG, Houston JB. 2006. Determination of a human hepatic microsomal scaling factor for predicting in vivo drug clearance. Pharm Res. 23(3):533–539.
   PubMed Web of Science ®Google Scholar
• Hallifax D, Foster JA, Houston JB. 2010. Prediction of human metabolic clearance from in vitro systems: retrospective analysis and prospective view. Pharm Res. 27(10):2150–2161.
   PubMed Web of Science ®Google Scholar
• Hallifax D, Houston J. 2009. Methodological uncertainty in quantitative prediction of human hepatic clearance from in vitro experimental systems. Curr Drug Metab. 10(3):307–321.
   PubMed Web of Science ®Google Scholar
• Hallifax D, Houston JB. 2006. Binding of drugs to hepatic microsomes: comment and assessment of current prediction methodology with recommendation for improvement. Drug Metab Dispos. 34(4):724–726.
   PubMed Web of Science ®Google Scholar
• Hallifax D, Houston JB. 2012. Evaluation of hepatic clearance prediction using in vitro data: emphasis on fraction unbound in plasma and drug ionisation using a database of 107 drugs. J Pharm Sci. 101(8):2645–2652.
   PubMed Web of Science ®Google Scholar
• Hallifax D, Houston JB. 2019. Use of segregated hepatocyte scaling factors and cross-species relationships to resolve clearance dependence in the prediction of human hepatic clearance. Drug Metab Dispos. 47(3):320–327.
   PubMed Web of Science ®Google Scholar
• Hallifax D, Rawden HC, Hakooz N, Houston JB. 2005. Prediction of metabolic clearance using cryopreserved human hepatocytes: kinetic characteristics for five benzodiazepines. Drug Metab Dispos. 33(12):1852–1858.
   PubMed Web of Science ®Google Scholar
• Hansen HH, Feigh M, Veidal SS, Rigbolt KT, Vrang N, Fosgerau K. 2017. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today. 22(11):1707–1718.
   PubMed Web of Science ®Google Scholar
• Harris JB, Hartman JH, Luz AL, Wilson JY, Dinyari A, Meyer JN. 2020. Zebrafish CYP1A expression in transgenic Caenorhabditis elegans protects from exposures to benzo[a]pyrene and a complex polycyclic aromatic hydrocarbon mixture. Toxicology. 440:152473.
   PubMed Web of Science ®Google Scholar
• Hartman JH, Widmayer SJ, Bergemann CM, King DE, Morton KS, Romersi RF, Jameson LE, Leung MCK, Andersen EC, Taubert S, et al. 2021. Xenobiotic metabolism and transport in Caenorhabditis elegans. J Toxicol Env Health. 24(2):51–94.
   Web of Science ®Google Scholar
• Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnai M, Wakui M, Ito M, Suematsu M, Peltz G, Nakamura M, et al. 2011. The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional. Biochem Biophys Res Commun. 405(3):405–410.
   PubMed Web of Science ®Google Scholar
• He C, Wan H. 2018. Drug metabolism and metabolite safety assessment in drug discovery and development. Expert Opin Drug Metab Toxicol. 14(10):1071–1085.
   PubMed Web of Science ®Google Scholar
• Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C, Muffato M, Collins JE, Humphray S, McLaren K, Matthews L, et al. 2013. The zebrafish reference genome sequence and its relationship to the human genome. Nature. 496(7446):498–503.
   PubMed Web of Science ®Google Scholar
• Hultman I, Vedin C, Abrahamsson A, Winiwarter S, Darnell M. 2016. Use of HμREL human coculture system for prediction of intrinsic clearance and metabolite formation for slowly metabolized compounds. Mol Pharm. 13(8):2796–2807.
   PubMed Web of Science ®Google Scholar
• Hunt PR. 2017. The C. elegans model in toxicity testing. J Appl Toxicol. 37(1):50–59.
   PubMed Web of Science ®Google Scholar
• Hunt PR, Olejnik N, Sprando RL. 2012. Toxicity ranking of heavy metals with screening method using adult Caenorhabditis elegans and propidium iodide replicates toxicity ranking in rat. Food Chem Toxicol. 50(9):3280–3290.
   PubMed Web of Science ®Google Scholar
• Hutzler JM, Ring BJ, Anderson SR. 2015. Low-turnover drug molecules: a current challenge for drug metabolism scientists. Drug Metab Dispos. 43(12):1917–1928.
   PubMed Web of Science ®Google Scholar
• Ingelman-Sundberg M, Lauschke VM. 2018. Human liver spheroids in chemically defined conditions for studies of gene–drug, drug–drug and disease–drug interactions. Pharmacogenomics. 19(14):1133–1138.
   PubMed Web of Science ®Google Scholar
• Ireson CR, Alavijeh MS, Palmer AM, Fowler ER, Jones HJ. 2019. The role of mouse tumour models in the discovery and development of anticancer drugs. Br J Cancer. 121(2):101–108.
   PubMed Web of Science ®Google Scholar
• Ito K, Houston JB. 2004. Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes. Pharm Res. 21(5):785–792.
   PubMed Web of Science ®Google Scholar
• Ito K, Houston JB. 2005. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res. 22(1):103–112.
   PubMed Web of Science ®Google Scholar
• Izumi S, Nozaki Y, Komori T, Takenaka O, Maeda K, Kusuhara H, Sugiyama Y. 2017. Comparison of the predictability of human hepatic clearance for organic anion transporting polypeptide substrate drugs between different in vitro–in vivo extrapolation approaches. J Pharm Sci. 106(9):2678–2687.
   PubMed Web of Science ®Google Scholar
• Jiang W, Dai T, Xie S, Ding L, Huang L, Dai R. 2020. Roles of diclofenac and its metabolites in immune activation associated with acute hepatotoxicity in TgCYP3A4/hPXR-humanized mice. Int Immunopharmacol. 86:106723.
   PubMed Web of Science ®Google Scholar
• Jin Y, Xia J, Pan Z, Yang J, Wang W, Fu Z. 2018. Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish. Environ Pollut. 235:322–329.
   PubMed Web of Science ®Google Scholar
• Johnson LSM. 2020. The trouble with animal models in brain research. In: Johnson LSM, Fenton A, Shriver A, editors. Neuroethics and nonhuman animals. Cham (Switzerland): Springer International Publishing; p. 271–286.
   Google Scholar
• Jones HM, Barton HA, Lai Y, Bi Y-A, Kimoto E, Kempshall S, Tate SC, El-Kattan A, Houston JB, Galetin A, et al. 2012. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Metab Dispos. 40(5):1007–1017.
   PubMed Web of Science ®Google Scholar
• Kamel A, Bowlin S, Hosea N, Arkilo D, Laurenza A. 2021. In vitro metabolism of slowly cleared GPR139 agonist TAK-041 using rat, dog, monkey and human hepatocyte models (HepatoPac): correlation with in vivo metabolism. Drug Metab Dispos. 49(2):121–132.
   PubMed Web of Science ®Google Scholar
• Kanebratt KP, Janefeldt A, Vilén L, Vildhede A, Samuelsson K, Milton L, Björkbom A, Persson M, Leandersson C, Andersson TB, et al. 2021. Primary human hepatocyte spheroid model as a 3D in vitro platform for metabolism studies. J Pharm Sci. 110(1):422–431.
   PubMed Web of Science ®Google Scholar
• Kantae V, Krekels EHJ, Ordas A, González O, van Wijk RC, Harms AC, Racz PI, van der Graaf PH, Spaink HP, Hankemeier T. 2016. Pharmacokinetic modeling of paracetamol uptake and clearance in zebrafish larvae: expanding the allometric scale in vertebrates with five orders of magnitude. Zebrafish. 13(6):504–510.
   PubMed Web of Science ®Google Scholar
• Keefer C, Chang G, Carlo A, Novak JJ, Banker M, Carey J, Cianfrogna J, Eng H, Jagla C, Johnson N, et al. 2020. Mechanistic insights on clearance and inhibition discordance between liver microsomes and hepatocytes when clearance in liver microsomes is higher than in hepatocytes. Eur J Pharm Sci. 155:105541.
   PubMed Web of Science ®Google Scholar
• Kendall LV, Owiny JR, Dohm ED, Knapek KJ, Lee ES, Kopanke JH, Fink M, Hansen SA, Ayers JD. 2018. Replacement, refinement, and reduction in animal studies with biohazardous agents. ILAR J. 59(2):177–194.
   PubMed Web of Science ®Google Scholar
• Khazaee M, Ng CA. 2018. Evaluating parameter availability for physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoic acid (PFOA) in zebrafish. Environ Sci Process Impacts. 20(1):105–119.
   PubMed Web of Science ®Google Scholar
• Khetani SR, Bhatia SN. 2008. Microscale culture of human liver cells for drug development. Nat Biotechnol. 26(1):120–126.
   PubMed Web of Science ®Google Scholar
• Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. 2009. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos. 37(1):82–89.
   PubMed Web of Science ®Google Scholar
• Kilkenny C, Parsons N, Kadyszewski E, Festing MF, Cuthill IC, Fry D, Hutton J, Altman DG. 2009. Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PLoS One. 4(11):e7824.
   PubMed Web of Science ®Google Scholar
• Kim S-J, Lee K-R, Miyauchi S, Sugiyama Y. 2019. Extrapolation of in vivo hepatic clearance from in vitro uptake clearance by suspended human hepatocytes for anionic drugs with high binding to human albumin: improvement of in vitro-to-in vivo extrapolation by considering the “albumin-mediated” hepatic uptake mechanism on the basis of the “facilitated-dissociation model”. Drug Metab Dispos. 47(2):94–103.
   PubMed Web of Science ®Google Scholar
• Kim SS, Im SH, Yang JY, Lee Y-R, Kim GR, Chae JS, Shin D-S, Song JS, Ahn S, Lee BH, et al. 2017. Zebrafish as a screening model for testing the permeability of blood–brain barrier to small molecules. Zebrafish. 14(4):322–330.
   PubMed Web of Science ®Google Scholar
• Kimoto E, Bi Y-A, Kosa RE, Tremaine LM, Varma MV. 2017. Hepatobiliary clearance prediction: species scaling from monkey, dog, and rat, and in vitro–in vivo extrapolation of sandwich-cultured human hepatocytes using 17 drugs. J Pharm Sci. 106(9):2795–2804.
   PubMed Web of Science ®Google Scholar
• Kimoto E, Yoshida K, Balogh LM, Bi Y-a, Maeda K, El-Kattan A, Sugiyama Y, Lai Y. 2012. Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. Mol Pharm. 9(12):3535–3542.
   PubMed Web of Science ®Google Scholar
• King EG, Kislukhin G, Walters KN, Long AD. 2014. Using Drosophila melanogaster to identify chemotherapy toxicity genes. Genetics. 198(1):31–43.
   PubMed Web of Science ®Google Scholar
• Komori Y, Iwashita Y, Ohta M, Kawano Y, Inomata M, Kitano S. 2014. Effects of different pressure levels of CO2 pneumoperitoneum on liver regeneration after liver resection in a rat model. Surg Endosc. 28(8):2466–2473.
   PubMed Web of Science ®Google Scholar
• Korzekwa K, Nagar S. 2017. On the nature of physiologically-based pharmacokinetic models–a priori or a posteriori? Mechanistic or empirical? Pharm Res. 34(3):529–534.
   PubMed Web of Science ®Google Scholar
• Kratochwil NA, Meille C, Fowler S, Klammers F, Ekiciler A, Molitor B, Simon S, Walter I, McGinnis C, Walther J, et al. 2017. Metabolic profiling of human long-term liver models and hepatic clearance predictions from in vitro data using nonlinear mixed-effects modeling. AAPS J. 19(2):534–550.
   PubMed Web of Science ®Google Scholar
• Kulkarni P, Korzekwa K, Nagar S. 2016. Intracellular unbound atorvastatin concentrations in the presence of metabolism and transport. J Pharmacol Exp Ther. 359(1):26–36.
   PubMed Web of Science ®Google Scholar
• Kulkarni P, Korzekwa K, Nagar S. 2020. A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats. Xenobiotica. 50(5):536–544.
   PubMed Web of Science ®Google Scholar
• Kumar V, Salphati L, Hop CECA, Xiao G, Lai Y, Mathias A, Chu X, Humphreys WG, Liao M, Heyward S, et al. 2019. A comparison of total and plasma membrane abundance of transporters in suspended, plated, sandwich-cultured human hepatocytes versus human liver tissue using quantitative targeted proteomics and cell surface biotinylation. Drug Metab Dispos. 47(4):350–357.
   PubMed Web of Science ®Google Scholar
• Kumar V, Yin M, Ishida K, Salphati L, Hop CECA, Rowbottom C, Xiao G, Lai Y, Mathias A, Chu X, et al. 2021. Prediction of transporter-mediated rosuvastatin hepatic uptake clearance and drug interaction in humans using proteomics-informed REF approach. Drug Metab Dispos. 49(2):159–168.
   PubMed Web of Science ®Google Scholar
• Kunze A, Poller B, Huwyler J, Camenisch G. 2015. Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins. Drug Metab Pers Ther. 30(3):175–188.
   PubMedGoogle Scholar
• Lancett P, Williamson B, Barton P, Riley RJ. 2018. Development and characterization of a human hepatocyte low intrinsic clearance assay for use in drug discovery. Drug Metab Dispos. 46(8):1169–1178.
   PubMed Web of Science ®Google Scholar
• Lauschke VM, Hendriks DF, Bell CC, Andersson TB, Ingelman-Sundberg M. 2016. Novel 3D culture systems for studies of human liver function and assessments of the hepatotoxicity of drugs and drug candidates. Chem Res Toxicol. 29(12):1936–1955.
   PubMed Web of Science ®Google Scholar
• Lauschke VM, Shafagh RZ, Hendriks DF, Ingelman‐Sundberg M. 2019. 3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism, and toxicity: emerging culture paradigms and applications. Biotechnol J. 14(7):1800347.
   PubMed Web of Science ®Google Scholar
• Lauschke VM, Vorrink SU, Moro SML, Rezayee F, Nordling Å, Hendriks DFG, Bell CC, Sison-Young R, Park BK, Goldring CE, et al. 2016. Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation. Hepatology. 64(5):1743–1756.
   PubMed Web of Science ®Google Scholar
• Lee H, Pak YK, Yeo E-J, Kim YS, Paik HY, Lee SK. 2018. It is time to integrate sex as a variable in preclinical and clinical studies. Exp Mol Med. 50(7):1–2.
   Google Scholar
• Li N, Badrinarayanan A, Ishida K, Li X, Roberts J, Wang S, Hayashi M, Gupta A. 2020. Albumin-mediated uptake improves human clearance prediction for hepatic uptake transporter substrates aiding a mechanistic in vitro-in vivo extrapolation (IVIVE) strategy in discovery research. AAPS J. 23(1):1–15.
   PubMed Web of Science ®Google Scholar
• Li N, Badrinarayanan A, Li X, Roberts J, Hayashi M, Virk M, Gupta A. 2020. Comparison of in vitro to in vivo extrapolation approaches for predicting transporter-mediated hepatic uptake clearance using suspended rat hepatocytes. Drug Metab Dispos. 48(10):861–872.
   PubMed Web of Science ®Google Scholar
• Li Z, Lee SH, Jeong HJ, Kang HE. 2021. Pharmacokinetic changes of clozapine and norclozapine in a rat model of non-alcoholic fatty liver disease induced by orotic acid. Xenobiotica. 51(3):324–334.
   PubMed Web of Science ®Google Scholar
• Liang X, Park Y, DeForest N, Hao J, Zhao X, Niu C, Wang K, Smith B, Lai Y. 2020. In vitro hepatic uptake in human and monkey hepatocytes in the presence and absence of serum protein and its in vitro to in vivo extrapolation. Drug Metab Dispos. 48(12):1283–1292.
   PubMed Web of Science ®Google Scholar
• Liao M, Zhu Q, Zhu A, Gemski C, Ma B, Guan E, Li AP, Xiao G, Xia CQ. 2019. Comparison of uptake transporter functions in hepatocytes in different species to determine the optimal model for evaluating drug transporter activities in humans. Xenobiotica. 49(7):852–862.
   PubMed Web of Science ®Google Scholar
• Lin C, Khetani SR. 2016. Advances in engineered liver models for investigating drug-induced liver injury. BioMed Res Int. 2016:1–20.
   Web of Science ®Google Scholar
• Lin C, Shi J, Moore A, Khetani SR. 2016. Prediction of drug clearance and drug-drug interactions in microscale cultures of human hepatocytes. Drug Metab Dispos. 44(1):127–136.
   PubMed Web of Science ®Google Scholar
• Lin JH. 1995. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 23(10):1008–1021.
   PubMed Web of Science ®Google Scholar
• Louisse J, Alewijn M, Peijnenburg AA, Cnubben NH, Heringa MB, Coecke S, Punt A. 2020. Towards harmonization of test methods for in vitro hepatic clearance studies. Toxicol in Vitro. 63:104722.
   PubMed Web of Science ®Google Scholar
• Lu J, Chen A, Ma X, Shang X, Zhang Y, Guo Y, Liu M, Wang X. 2020. Generation and characterization of cytochrome P450 2J3/10 CRISPR/Cas9 knockout rat model. Drug Metab Dispos. 48(11):1129–1136.
   PubMed Web of Science ®Google Scholar
• Lundquist P, Lööf J, Sohlenius-Sternbeck A-K, Floby E, Johansson J, Bylund J, Hoogstraate J, Afzelius L, Andersson TB. 2014. The impact of solute carrier (SLC) drug uptake transporter loss in human and rat cryopreserved hepatocytes on clearance predictions. Drug Metab Dispos. 42(3):469–480.
   PubMed Web of Science ®Google Scholar
• Luque T, O’Reilly DR. 2002. Functional and phylogenetic analyses of a putative Drosophila melanogaster UDP-glycosyltransferase gene. Insect Biochem Mol Biol. 32(12):1597–1604.
   PubMed Web of Science ®Google Scholar
• Maitra U, Ciesla L. 2019. Using Drosophila as a platform for drug discovery from natural products in Parkinson’s disease. Medchemcomm. 10(6):867–879.
   PubMed Web of Science ®Google Scholar
• Mak IW, Evaniew N, Ghert M. 2014. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 6(2):114–118.
   PubMed Web of Science ®Google Scholar
• Martignoni M, Groothuis GM, de Kanter R. 2006. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2(6):875–894.
   PubMed Web of Science ®Google Scholar
• Martins PN, Theruvath TP, Neuhaus P. 2008. Rodent models of partial hepatectomies. Liver Int. 28(1):3–11.
   PubMed Web of Science ®Google Scholar
• Matilainen J, Mustonen A-M, Rilla K, Käkelä R, Sihvo SP, Nieminen P. 2020. Orotic acid-treated hepatocellular carcinoma cells resist steatosis by modification of fatty acid metabolism. Lipids Health Dis. 19(1):70.
   PubMed Web of Science ®Google Scholar
• McGill MR, Jaeschke H. 2019. Animal models of drug-induced liver injury. Biochim Biophys Acta. 1865(5):1031–1039.
   PubMed Web of Science ®Google Scholar
• McGinnity DF, Soars MG, Urbanowicz RA, Riley RJ. 2004. Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos. 32(11):1247–1253.
   PubMed Web of Science ®Google Scholar
• McGrath P, Li C-Q. 2008. Zebrafish: a predictive model for assessing drug-induced toxicity. Drug Discov Today. 13(9–10):394–401.
   PubMed Web of Science ®Google Scholar
• Ménochet K, Kenworthy KE, Houston JB, Galetin A. 2012a. Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model. J Pharmacol Exp Ther. 341(1):2–15.
   PubMed Web of Science ®Google Scholar
• Ménochet K, Kenworthy KE, Houston JB, Galetin A. 2012b. Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes. Drug Metab Dispos. 40(9):1744–1756.
   PubMed Web of Science ®Google Scholar
• Menzel R, Bogaert T, Achazi R. 2001. A systematic gene expression screen of Caenorhabditis elegans cytochrome P450 genes reveals CYP35 as strongly xenobiotic inducible. Arch Biochem Biophys. 395(2):158–168.
   PubMed Web of Science ®Google Scholar
• Messner S, Fredriksson L, Lauschke VM, Roessger K, Escher C, Bober M, Kelm JM, Ingelman-Sundberg M, Moritz W. 2018. Transcriptomic, proteomic, and functional long-term characterization of multicellular three-dimensional human liver microtissues. Appl in Vitro Toxicol. 4(1):1–12.
   PubMedGoogle Scholar
• Miranda JP, Serras AS, Rodrigues JS, Cipriano M, Rodrigues AV, Oliveira NG. 2021. A critical perspective on 3D liver models for drug metabolism and toxicology studies. Front Cell Dev Biol. 9:626805.
   PubMed Web of Science ®Google Scholar
• Miura T, Uehara S, Shimizu M, Murayama N, Utoh M, Suemizu H, Yamazaki H. 2020. Different roles of human cytochrome P450 2C9 and 3A enzymes in diclofenac 4′-and 5-hydroxylations mediated by metabolically inactivated human hepatocytes in previously transplanted chimeric mice. Chem Res Toxicol. 33(2):634–639.
   PubMed Web of Science ®Google Scholar
• Miyauchi S, Masuda M, Kim S-J, Tanaka Y, Lee K-R, Iwakado S, Nemoto M, Sasaki S, Shimono K, Tanaka Y, et al. 2018. The phenomenon of albumin-mediated hepatic uptake of organic anion transport polypeptide substrates: prediction of the in vivo uptake clearance from the in vitro uptake by isolated hepatocytes using a facilitated-dissociation model. Drug Metab Dispos. 46(3):259–267.
   PubMed Web of Science ®Google Scholar
• Mizoi K, Arakawa H, Yano K, Koyama S, Kojima H, Ogihara T. 2020. Utility of three-dimensional cultures of primary human hepatocytes (spheroids) as pharmacokinetic models. Biomedicines. 8(10):374.
   PubMed Web of Science ®Google Scholar
• Mizoi K, Hosono M, Kojima H, Ogihara T. 2020. Establishment of a primary human hepatocyte spheroid system for evaluating metabolic toxicity using dacarbazine under conditions of CYP1A2 induction. Drug Metab Pharmacokinet. 35(2):201–206.
   PubMed Web of Science ®Google Scholar
• Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. 2001. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab Dispos. 29(10):1316–1324.
   PubMed Web of Science ®Google Scholar
• Neuhoff S, Artursson P, Zamora I, Ungell A-L. 2006. Impact of extracellular protein binding on passive and active drug transport across Caco-2 cells. Pharm Res. 23(2):350–359.
   PubMed Web of Science ®Google Scholar
• Neyshaburinezhad N, Seidabadi M, Rouini M, Lavasani H, Foroumadi A, Ardakani YH. 2020. Evaluation of hepatic CYP2D1 activity and hepatic clearance in type I and type II diabetic rat models, before and after treatment with insulin and metformin. DARU J Pharma Sci. 28:479–487.
   Web of Science ®Google Scholar
• Obach RS. 1997. Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol. Drug Metab Dispos. 25(12):1359–1369.
   PubMed Web of Science ®Google Scholar
• Obach RS. 1999. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos. 27(11):1350–1359.
   PubMed Web of Science ®Google Scholar
• Oh Y, Jeong Y-S, Kim M-S, Min JS, Ryoo G, Park JE, Jun Y, Song Y-K, Chun S-E, Han S, et al. 2018. Inhibition of organic anion transporting polypeptide 1B1 and 1B3 by betulinic acid: effects of preincubation and albumin in the media. J Pharm Sci. 107(6):1713–1723.
   PubMed Web of Science ®Google Scholar
• Ohkura T, Ohta K, Nagao T, Kusumoto K, Koeda A, Ueda T, Jomura T, Ikeya T, Ozeki E, Wada K, et al. 2014. Evaluation of human hepatocytes cultured by three-dimensional spheroid systems for drug metabolism. Drug Metab Pharmacokinet. 29(5):373–378.
   PubMed Web of Science ®Google Scholar
• Országhová Z, Uličná O, Liptáková A, Žitňanová I, Muchová J, Watala C, Ďuračková Z. 2012. Effects of N1-methylnicotinamide on oxidative and glycooxidative stress markers in rats with streptozotocin-induced diabetes mellitus. Redox Rep. 17(1):1–7.
   PubMed Web of Science ®Google Scholar
• Pandey UB, Nichols CD. 2011. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev. 63(2):411–436.
   PubMed Web of Science ®Google Scholar
• Pang KS, Han YR, Noh K, Lee PI, Rowland M. 2019. Hepatic clearance concepts and misconceptions: why the well-stirred model is still used even though it is not physiologic reality? Biochem Pharmacol. 169:113596.
   PubMed Web of Science ®Google Scholar
• Patilea-Vrana GI, Unadkat JD. 2018. When does the rate-determining step in the hepatic clearance of a drug switch from sinusoidal uptake to all hepatobiliary clearances? Implications for predicting drug-drug interactions. Drug Metab Dispos. 46(11):1487–1496.
   PubMed Web of Science ®Google Scholar
• Pelkonen O, Turpeinen M. 2007. In vitro-in vivo extrapolation of hepatic clearance: biological tools, scaling factors, model assumptions and correct concentrations. Xenobiotica. 37(10-11):1066–1089.
   PubMed Web of Science ®Google Scholar
• Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS. 2007. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 334(7586):197.
   PubMed Web of Science ®Google Scholar
• Poon KL, Wang X, Ng AS, Goh WH, McGinnis C, Fowler S, Carney TJ, Wang H, Ingham PW. 2017. Humanizing the zebrafish liver shifts drug metabolic profiles and improves pharmacokinetics of CYP3A4 substrates. Arch Toxicol. 91(3):1187–1197.
   PubMed Web of Science ®Google Scholar
• Poulin P. 2013. Prediction of total hepatic clearance by combining metabolism, transport, and permeability data in the in vitro–in vivo extrapolation methods: emphasis on an apparent fraction unbound in liver for drugs. J Pharm Sci. 102(7):2085–2095.
   PubMed Web of Science ®Google Scholar
• Poulin P, Burczynski FJ, Haddad S. 2016. The role of extracellular binding proteins in the cellular uptake of drugs: impact on quantitative in vitro-to-in vivo extrapolations of toxicity and efficacy in physiologically based pharmacokinetic-pharmacodynamic research. J Pharm Sci. 105(2):497–508.
   PubMed Web of Science ®Google Scholar
• Poulin P, Hop CE, Ho Q, Halladay JS, Haddad S, Kenny JR. 2012. Comparative assessment of in vitro–in vivo extrapolation methods used for predicting hepatic metabolic clearance of drugs. J Pharm Sci. 101(11):4308–4326.
   PubMed Web of Science ®Google Scholar
• Poulin P, Kenny JR, Hop CE, Haddad S. 2012. In vitro–in vivo extrapolation of clearance: modeling hepatic metabolic clearance of highly bound drugs and comparative assessment with existing calculation methods. J Pharm Sci. 101(2):838–851.
   PubMed Web of Science ®Google Scholar
• Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I. 2004. Where is the evidence that animal research benefits humans? BMJ. 328(7438):514–517.
   PubMed Web of Science ®Google Scholar
• Prasad B, Evers R, Gupta A, Hop CE, Salphati L, Shukla S, Ambudkar SV, Unadkat JD. 2014. Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metab Dispos. 42(1):78–88.
   PubMed Web of Science ®Google Scholar
• Prior N, Inacio P, Huch M. 2019. Liver organoids: from basic research to therapeutic applications. Gut. 68(12):2228–2237.
   PubMed Web of Science ®Google Scholar
• Qiao R, Sheng C, Lu Y, Zhang Y, Ren H, Lemos B. 2019. Microplastics induce intestinal inflammation, oxidative stress, and disorders of metabolome and microbiome in zebrafish. Sci Total Environ. 662:246–253.
   PubMed Web of Science ®Google Scholar
• Rennekamp AJ, Peterson RT. 2015. 15 years of zebrafish chemical screening. Curr Opin Chem Biol. 24:58–70.
   PubMed Web of Science ®Google Scholar
• Riccardi K, Lin J, Li Z, Niosi M, Ryu S, Hua W, Atkinson K, Kosa RE, Litchfield J, Di L. 2017. Novel method to predict in vivo liver-to-plasma Kpuu for OATP substrates using suspension hepatocytes. Drug Metab Dispos. 45(5):576–580.
   PubMed Web of Science ®Google Scholar
• Riccardi K, Ryu S, Lin J, Yates P, Tess D, Li R, Singh D, Holder BR, Kapinos B, Chang G, et al. 2018. Comparison of species and cell-type differences in fraction unbound of liver tissues, hepatocytes, and cell lines. Drug Metab Dispos. 46(4):415–421.
   PubMed Web of Science ®Google Scholar
• Riccardi K, Ryu S, Tess D, Li R, Luo L, Johnson N, Jordan S, Patel R, Di L. 2020. Comparison of fraction unbound between liver homogenate and hepatocytes at 4 °C. AAPS J. 22(4):1–9.
   Web of Science ®Google Scholar
• Richardson SJ, Bai A, Kulkarni AA, Moghaddam MF. 2016. Efficiency in drug discovery: liver S9 fraction assay as a screen for metabolic stability. Drug Metab Lett. 10(2):83–90.
   PubMedGoogle Scholar
• Riede J, Camenisch G, Huwyler J, Poller B. 2017. Current in vitro methods to determine hepatic Kpuu: a comparison of their usefulness and limitations. J Pharm Sci. 106(9):2805–2814.
   PubMed Web of Science ®Google Scholar
• Riede J, Wollmann BM, Molden E, Ingelman-Sundberg M. 2021. Primary human hepatocyte spheroids as an in vitro tool for investigating drug compounds with low clearance. Drug Metab Dispos.
   PubMed Web of Science ®Google Scholar
• Riley RJ, McGinnity DF, Austin RP. 2005. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metab Dispos. 33(9):1304–1311.
   PubMed Web of Science ®Google Scholar
• Rowe C, Goldring CE, Kitteringham NR, Jenkins RE, Lane BS, Sanderson C, Elliott V, Platt V, Metcalfe P, Park BK. 2010. Network analysis of primary hepatocyte dedifferentiation using a shotgun proteomics approach. J Proteome Res. 9(5):2658–2668.
   PubMed Web of Science ®Google Scholar
• Rowland M, Benet LZ, Graham GG. 1973. Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm. 1(2):123–136.
   PubMedGoogle Scholar
• Rowland A, Gaganis P, Elliot DJ, Mackenzie PI, Knights KM, Miners JO. 2007. Binding of inhibitory fatty acids is responsible for the enhancement of UDP-glucuronosyltransferase 2B7 activity by albumin: implications for in vitro-in vivo extrapolation. J Pharmacol Exp Ther. 321(1):137–147.
   PubMed Web of Science ®Google Scholar
• Rowland A, Knights KM, Mackenzie PI, Miners JO. 2008. The “albumin effect” and drug glucuronidation: bovine serum albumin and fatty acid-free human serum albumin enhance the glucuronidation of UDP-glucuronosyltransferase (UGT) 1A9 substrates but not UGT1A1 and UGT1A6 activities. Drug Metab Dispos. 36(6):1056–1062.
   PubMed Web of Science ®Google Scholar
• Saad M, Matheeussen A, Bijttebier S, Verbueken E, Pype C, Casteleyn C, Van Ginneken C, Apers S, Maes L, Cos P, et al. 2017. In vitro CYP-mediated drug metabolism in the zebrafish (embryo) using human reference compounds. Toxicol in Vitro. 42:329–336.
   PubMed Web of Science ®Google Scholar
• Saracyn M, Zdanowski R, Brytan M, Kade G, Nowak Z, Patera J, Dyrla P, Gil J, Wańkowicz Z. 2015. D-galactosamine intoxication in experimental animals: is it only an experimental model of acute liver failure? Med Sci Monit. 21:1469–1477.
   PubMed Web of Science ®Google Scholar
• Saravanakumar A, Sadighi A, Ryu R, Akhlaghi F. 2019. Physicochemical properties, biotransformation, and transport pathways of established and newly approved medications: a systematic review of the top 200 most prescribed drugs vs. the FDA-approved drugs between 2005 and 2016. Clin Pharmacokinet. 58(10):1281–1294.
   PubMed Web of Science ®Google Scholar
• Scott TA, Quintaneiro LM, Norvaisas P, Lui PP, Wilson MP, Leung K-Y, Herrera-Dominguez L, Sudiwala S, Pessia A, Clayton PT, et al. 2017. Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans. Cell. 169(3):442–456.
   PubMed Web of Science ®Google Scholar
• Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L. et al. 2013. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 110(9):3507–3512.
   PubMed Web of Science ®Google Scholar
• Shah RR, Smith RL. 2015. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos. 43(3):400–410.
   PubMed Web of Science ®Google Scholar
• Shen JX, Youhanna S, Zandi Shafagh R, Kele J, Lauschke VM. 2020. Organotypic and microphysiological models of liver, gut, and kidney for studies of drug metabolism, pharmacokinetics, and toxicity. Chem Res Toxicol. 33(1):38–60.
   PubMed Web of Science ®Google Scholar
• Shibata Y, Takahashi H, Chiba M, Ishii Y. 2002. Prediction of hepatic clearance and availability by cryopreserved human hepatocytes: an application of serum incubation method. Drug Metab Dispos. 30(8):892–896.
   PubMed Web of Science ®Google Scholar
• Siméon S, Brotzmann K, Fisher C, Gardner I, Silvester S, Maclennan R, Walker P, Braunbeck T, Bois FY. 2020. Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs. Reprod Toxicol. 93:219–229.
   PubMed Web of Science ®Google Scholar
• Sirianni GL, Pang KS. 1997. Organ clearance concepts: new perspectives on old principles. J Pharmacokinet Biopharma. 25(4):449–470.
   PubMedGoogle Scholar
• Soars MG, Grime K, Sproston JL, Webborn PJ, Riley RJ. 2007. Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metab Dispos. 35(6):859–865.
   PubMed Web of Science ®Google Scholar
• Sodhi JK, Benet LZ. 2021. Successful and unsuccessful prediction of human hepatic clearance for lead optimization. J Med Chem. 64(7):3546–3559.
   PubMed Web of Science ®Google Scholar
• Sodhi JK, Liu S, Benet LZ. 2020. Challenging the relevance of unbound tissue-to-blood partition coefficient (Kp uu) on prediction of drug-drug interactions. Pharm Res. 37(4):1–10.
   Web of Science ®Google Scholar
• Sodhi JK, Wang H-J, Benet LZ. 2020. Are there any experimental perfusion data that preferentially support the dispersion and parallel-tube models over the well-stirred model of organ elimination? Drug Metab Dispos. 48(7):537–543.
   PubMed Web of Science ®Google Scholar
• Sohlenius-Sternbeck A-K. 2006. Determination of the hepatocellularity number for human, dog, rabbit, rat and mouse livers from protein concentration measurements. Toxicol in Vitro. 20(8):1582–1586.
   PubMed Web of Science ®Google Scholar
• Strähle U, Scholz S, Geisler R, Greiner P, Hollert H, Rastegar S, Schumacher A, Selderslaghs I, Weiss C, Witters H, et al. 2012. Zebrafish embryos as an alternative to animal experiments—a commentary on the definition of the onset of protected life stages in animal welfare regulations. Reprod Toxicol. 33(2):128–132.
   PubMed Web of Science ®Google Scholar
• Strange K. 2016. Drug discovery in fish, flies, and worms. ILAR J. 57(2):133–143.
   PubMed Web of Science ®Google Scholar
• Stringer R, Nicklin P, Houston J. 2008. Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance. Xenobiotica. 38(10):1313–1329.
   PubMed Web of Science ®Google Scholar
• Tada K, Iwashita Y, Shiraiwa K, Uchida H, Oshima Y, Sato Y, Nakanuma H, Hirashita T, Masuda T, Endo Y, et al. 2020. Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model. Cancer Chemother Pharmacol. 85(2):345–352.
   PubMed Web of Science ®Google Scholar
• Tannenbaum J, Bennett BT. 2015. Russell and Burch’s 3Rs then and now: the need for clarity in definition and purpose. J Am Assoc Lab Anim Sci. 54(2):120–132.
   PubMed Web of Science ®Google Scholar
• Toth EL, Clarke JD, Csanaky IL, Cherrington NJ. 2020. Interaction of Oatp1b2 expression and nonalcoholic steatohepatitis on pravastatin plasma clearance. Biochem Pharmacol. 174:113780.
   PubMed Web of Science ®Google Scholar
• Tsao SC, Sugiyama Y, Sawada Y, Iga T, Hanano M. 1988. Kinetic analysis of albumin-mediated uptake of warfarin by perfused rat liver. J Pharmacokinet Biopharma. 16(2):165–181.
   PubMedGoogle Scholar
• Turpeinen M, Ghiciuc C, Opritoui M, Tursas L, Pelkonen O, Pasanen M. 2007. Predictive value of animal models for human cytochrome P450 (CYP)-mediated metabolism: a comparative study in vitro. Xenobiotica. 37(12):1367–1377.
   PubMed Web of Science ®Google Scholar
• Umehara K, Cantrill C, Wittwer MB, Di Lenarda E, Klammers F, Ekiciler A, Parrott N, Fowler S, Ullah M. 2020. Application of the extended clearance classification system (ECCS) in drug discovery and development: selection of appropriate in vitro tools and clearance prediction. Drug Metab Dispos. 48(10):849–860.
   PubMed Web of Science ®Google Scholar
• Umehara K-i, Camenisch G. 2012. Novel in vitro-in vivo extrapolation (IVIVE) method to predict hepatic organ clearance in rat. Pharm Res. 29(2):603–617.
   PubMed Web of Science ®Google Scholar
• Underhill GH, Khetani SR. 2018. Advances in engineered human liver platforms for drug metabolism studies. Drug Metab Dispos. 46(11):1626–1637.
   PubMed Web of Science ®Google Scholar
• van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, Macleod MR. 2010. Can animal models of disease reliably inform human studies? PLoS Med. 7(3):e1000245.
   PubMed Web of Science ®Google Scholar
• Van Norman GA. 2019. Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach? Basic Transl Sci. 4(7):845–854.
   PubMedGoogle Scholar
• van Wijk RC, Hu W, Dijkema SM, van den Berg DJ, Liu J, Bahi R, Verbeek FJ, Simonsson USH, Spaink HP, van der Graaf PH, et al. 2020. Anti-tuberculosis effect of isoniazid scales accurately from zebrafish to humans. Br J Pharmacol. 177(24):5518–5533.
   PubMed Web of Science ®Google Scholar
• van Wijk RC, Krekels EHJ, Hankemeier T, Spaink HP, van der Graaf PH. 2016. Systems pharmacology of hepatic metabolism in zebrafish larvae. Drug Discovery Today. 22:27–34.
   Google Scholar
• van Wijk RC, Krekels EHJ, Kantae V, Ordas A, Kreling T, Harms AC, Hankemeier T, Spaink HP, van der Graaf PH. 2019. Mechanistic and quantitative understanding of pharmacokinetics in zebrafish larvae through nanoscale blood sampling and metabolite modeling of paracetamol. J Pharmacol Exp Ther. 371(1):15–24.
   PubMed Web of Science ®Google Scholar
• Vildhede A, Kimoto E, Rodrigues AD, Varma MV. 2018. Quantification of hepatic organic anion transport proteins OAT2 and OAT7 in human liver tissue and primary hepatocytes. Mol Pharmaceutics. 15(8):3227–3235.
   PubMed Web of Science ®Google Scholar
• Vildhede A, Wiśniewski JR, Norén A, Karlgren M, Artursson P, 2015. Comparative proteomic analysis of human liver tissue and isolated hepatocytes with a focus on proteins determining drug exposure. J Proteome Res. 14(8):3305–3314.
   PubMed Web of Science ®Google Scholar
• Vorrink SU, Ullah S, Schmidt S, Nandania J, Velagapudi V, Beck O, Ingelman‐Sundberg M, Lauschke VM. 2017. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long‐term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics. The FASEB J. 31(6):2696–2708.
   PubMed Web of Science ®Google Scholar
• Wang L, Prasad B, Salphati L, Chu X, Gupta A, Hop CE, Evers R, Unadkat JD. 2015. Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab Dispos. 43(3):367–374.
   PubMed Web of Science ®Google Scholar
• Wang WW, Khetani SR, Krzyzewski S, Duignan DB, Obach RS. 2010. Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites. Drug Metab Dispos. 38(10):1900–1905.
   PubMed Web of Science ®Google Scholar
• Wang X, Shen M, Zhou J, Jin Y. 2019. Chlorpyrifos disturbs hepatic metabolism associated with oxidative stress and gut microbiota dysbiosis in adult zebrafish. Comp Biochem Physiol C: Toxicol Pharmacol. 216:19–28.
   PubMed Web of Science ®Google Scholar
• Wang Y, Moussian B, Schaeffeler E, Schwab M, Nies AT. 2018. The fruit fly Drosophila melanogaster as an innovative preclinical ADME model for solute carrier membrane transporters, with consequences for pharmacology and drug therapy. Drug Discovery Today. 23(10):1746–1760.
   PubMed Web of Science ®Google Scholar
• Wang Y-M, Hu X-Q, Xue Y, Li Z-J, Yanagita T, Xue C-H. 2011. Study on possible mechanism of orotic acid–induced fatty liver in rats. Nutrition. 27(5):571–575.
   PubMed Web of Science ®Google Scholar
• Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, Sugiyama Y. 2010. Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos. 38(2):215–222.
   PubMed Web of Science ®Google Scholar
• Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y. 2009. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther. 328(2):652–662.
   PubMed Web of Science ®Google Scholar
• Wegler C, Matsson P, Krogstad V, Urdzik J, Christensen H, Andersson TB, Artursson P. 2021. Influence of proteome profiles and intracellular drug exposure on differences in CYP activity in donor-matched human liver microsomes and hepatocytes. Mol Pharma. 18(4):1792–1805.
   PubMed Web of Science ®Google Scholar
• Weisiger R, Gollan J, Ockner R. 1981. Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin-bound substances. Science. 211(4486):1048–1051.
   PubMed Web of Science ®Google Scholar
• Wendler A, Wehling M. 2012. Translatability scoring in drug development: eight case studies. J Transl Med. 10(1):1–11.
   PubMed Web of Science ®Google Scholar
• Westlind-Johnsson A, Malmebo S, Johansson A, Otter C, Andersson TB, Johansson I, Edwards RJ, Boobis AR, Ingelman-Sundberg M. 2003. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos. 31(6):755–761.
   PubMed Web of Science ®Google Scholar
• Wilkinson GR, Shand DG. 1975. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 18(4):377–390.
   PubMed Web of Science ®Google Scholar
• Williams PL, Dusenbery DB. 1988. Using the nematode Caenorhabditis elegans to predict mammalian acute lethality to metallic salts. Toxicol Ind Health. 4(4):469–478.
   PubMed Web of Science ®Google Scholar
• Williamson B, Harlfinger S, McGinnity DF. 2020. Evaluation of the disconnect between hepatocyte and microsome intrinsic clearance and in vitro in vivo extrapolation performance. Drug Metab Dispos. 48(11):1137–1146.
   PubMed Web of Science ®Google Scholar
• Willoughby LF, Schlosser T, Manning SA, Parisot JP, Street IP, Richardson HE, Humbert PO, Brumby AM. 2013. An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery. Dis Models Mech. 6(2):521–529.
   PubMed Web of Science ®Google Scholar
• Wilson Z, Rostami‐Hodjegan A, Burn J, Tooley A, Boyle J, Ellis S, Tucker G. 2003. Inter‐individual variability in levels of human microsomal protein and hepatocellularity per gram of liver. Br J Clin Pharmacol. 56(4):433–440.
   PubMed Web of Science ®Google Scholar
• Wood FL, Houston JB, Hallifax D. 2017. Clearance prediction methodology needs fundamental improvement: trends common to rat and human hepatocytes/microsomes and implications for experimental methodology. Drug Metab Dispos. 45(11):1178–1188.
   PubMed Web of Science ®Google Scholar
• Wood FL, Houston JB, Hallifax D. 2018. Importance of the unstirred water layer and hepatocyte membrane integrity in vitro for quantification of intrinsic metabolic clearance. Drug Metab Dispos. 46(3):268–278.
   PubMed Web of Science ®Google Scholar
• Yabe Y, Galetin A, Houston JB. 2011. Kinetic characterization of rat hepatic uptake of 16 actively transported drugs. Drug Metab Dispos. 39(10):1808–1814.
   PubMed Web of Science ®Google Scholar
• Yamagata T, Zanelli U, Gallemann D, Perrin D, Dolgos H, Petersson C. 2017. Comparison of methods for the prediction of human clearance from hepatocyte intrinsic clearance for a set of reference compounds and an external evaluation set. Xenobiotica. 47(9):741–751.
   PubMed Web of Science ®Google Scholar
• Yokoi T, Oda S. 2021. Models of idiosyncratic drug-induced liver injury. Annu Rev Pharmacol Toxicol. 61(1):247–268.
   PubMed Web of Science ®Google Scholar
• Yoshikado T, Toshimoto K, Nakada T, Ikejiri K, Kusuhara H, Maeda K, Sugiyama Y. 2017. Comparison of methods for estimating unbound intracellular-to-medium concentration ratios in rat and human hepatocytes using statins. Drug Metab Dispos. 45(7):779–789.
   PubMed Web of Science ®Google Scholar
• Zamek-Gliszczynski MJ, Taub ME, Chothe PP, Chu X, Giacomini KM, Kim RB, Ray AS, Stocker SL, Unadkat JD, Wittwer MB. et al. 2018. Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance. Clin Pharmacol Ther. 104(5):890–899.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Tang W. 2018. Drug metabolism in drug discovery and development. Acta Pharmaceutica Sinica B. 8(5):721–732.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Shen JX, Lauschke VM. 2019. Comprehensive evaluation of organotypic and microphysiological liver models for prediction of drug-induced liver injury. Front Pharmacol. 10:1093.
   PubMed Web of Science ®Google Scholar
• Zucker I, Beery AK. 2010. Males still dominate animal studies. Nature. 465(7299):690–690.
   PubMed Web of Science ®Google Scholar