953
Views
7
CrossRef citations to date
0
Altmetric
Reviews

Plasma protein-mediated uptake and contradictions to the free drug hypothesis: a critical review

ORCID Icon, ORCID Icon & ORCID Icon
Pages 205-238 | Received 20 Oct 2022, Accepted 02 Mar 2023, Published online: 12 Apr 2023

References

  • Agarwal P, Ishida K, Reid DL, Gupta A. 2021. Clearance prediction for Amgen molecules against Extended Clearance Classification System (ECCS) and future directions. Drug Discov Today. 26(1):10–16.
  • Avdeef A, Artursson P, Neuhoff S, Lazorova L, Grasjo J, Tavelin S. 2005. Caco-2 permeability of weakly basic drugs predicted with the double-sink PAMPA pKa(flux) method. Eur J Pharm Sci. 24(4):333–349.
  • Baik J, Huang Y. 2016. Transporter-induced protein binding shift (TIPBS) hypothesis and modeling. 20th North American ISSX Meeting; Orlando, FL, USA.
  • Baker KJ, Bradley SE. 1966. Binding of sulfobromophthalein (BSP) sodium by plasma albumin. Its role in hepatic BSP extraction. J Clin Invest. 45(2):281–287.
  • Baker M, Parton T. 2007. Kinetic determinants of hepatic clearance: plasma protein binding and hepatic uptake. Xenobiotica. 37(10–11):1110–1134.
  • Barry PH, Diamond JM. 1984. Effects of unstirred layers on membrane phenomena. Physiol Rev. 64(3):763–872.
  • Bass L, Pond SM. 1988. The puzzle of rates of cellular uptake of protein-bound ligands. In: A. P, A. R, editors. Pharmacokinetics: mathematical and statistical approaches to metabolism and distribution of chemicals and drugs. p. 245–269.
  • Benet LZ, Sodhi JK. 2022. Can in vitro-in vivo extrapolation be successful? Recognizing the incorrect clearance assumptions. Clin Pharmacol Ther. 111(5):1022–1035.
  • Benet LZ, Sodhi JK, Makrygiorgos G, Mesbah A. 2021. There is only one valid definition of clearance: critical examination of clearance concepts reveals the potential for errors in clinical drug dosing decisions. AAPS J. 23(3):67.
  • 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.
  • Berezhkovskiy LM, Liu N, Halladay JS. 2012. Consistency of the novel equations for determination of hepatic clearance and drug time course in liver that account for the difference in drug ionization in extracellular and intracellular tissue water. J Pharm Sci. 101(2):516–518.
  • Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT. 2015. The role of albumin receptors in regulation of albumin homeostasis: implications for drug delivery. J Control Release. 211:144–162.
  • Besseghir K, Mosig D, Roch-Ramel F. 1989. Facilitation by serum albumin of renal tubular secretion of organic anions. Am J Physiol. 256(3 Pt 2):F475–F484.
  • Bi YA, Ryu S, Tess DA, Rodrigues AD, Varma MVS. 2021. Effect of human plasma on hepatic uptake of organic anion-transporting polypeptide 1B substrates: studies using transfected cells and primary human hepatocytes. Drug Metab Dispos. 49(1):72–83.
  • Bounakta S, Bteich M, Mantha M, Poulin P, Haddad S. 2018. Predictions of bisphenol A hepatic clearance in the isolated perfused rat liver (IPRL): impact of albumin binding and of co-administration with naproxen. Xenobiotica. 48(2):135–147.
  • Bow DA, Perry JL, Simon JD, Pritchard JB. 2006. The impact of plasma protein binding on the renal transport of organic anions. J Pharmacol Exp Ther. 316(1):349–355.
  • Bowman CM, Benet LZ. 2018. An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation. Eur J Pharm Sci. 123:502–514.
  • Bowman CM, Chen B, Cheong J, Liu L, Chen Y, Mao J. 2021. Improving the translation of organic anion transporting polypeptide substrates using HEK293 cell data in the presence and absence of human plasma via physiologically based pharmacokinetic modeling. Drug Metab Dispos. 49(7):530–539.
  • Bowman CM, Chen E, Chen L, Chen YC, 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.
  • 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.
  • Bteich M. 2019. An overview of albumin and alpha-1-acid glycoprotein main characteristics: highlighting the roles of amino acids in binding kinetics and molecular interactions. Heliyon. 5(11):e02879.
  • 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.
  • Bteich M, Poulin P, Haddad S. 2021. Comparative assessment of extrapolation methods based on the conventional free drug hypothesis and plasma protein-mediated hepatic uptake theory for the hepatic clearance predictions of two drugs extensively bound to both the albumin and alpha-1-acid glycoprotein. J Pharm Sci. 110(3):1385–1391.
  • Bteich M, Poulin P, Piette S, Haddad S. 2020. Impact of extensive plasma protein binding on the in situ hepatic uptake and clearance of perampanel and fluoxetine in Sprague Dawley rats. J Pharm Sci. 109(10):3190–3205.
  • Budhu AS, Noy N. 2002. Direct channeling of retinoic acid between cellular retinoic acid-binding protein II and retinoic acid receptor sensitizes mammary carcinoma cells to retinoic acid-induced growth arrest. Mol Cell Biol. 22(8):2632–2641.
  • Burczynski FJ, Cai ZS, Moran JB, Geisbuhler T, Rovetto M. 1995. Palmitate uptake by cardiac myocytes and endothelial cells. Am J Physiol. 168(4):1659–1666.
  • Burczynski FJ, Luxon BA. 1995. Is there facilitated uptake of fatty acids by the liver? Interpretation and analysis of experimental data. Can J Physiol Pharmacol. 73(4):409–420.
  • Burczynski FJ, Moran JB, Cai ZS, Forker EL. 1990. β-Lactoglobulin enhances the uptake of free palmitate by hepatocyte monolayers: the relative importance of diffusion and facilitated dissociation. Can J Physiol Pharmacol. 68(2):201–206.
  • Burczynski FJ, Wang GQ, Elmadhoun B, She YM, Roberts MS, Standing KG. 2001. Hepatocyte [3H]-palmitate uptake: effect of albumin surface charge modification. Can J Physiol Pharmacol. 79(10):868–875.
  • Burczynski FJ, Wang GQ, Hnatowich M. 1997. Effect of binding protein surface charge on palmitate uptake by hepatocyte suspensions. Br J Pharmacol. 120(7):1215–1220.
  • Cai X, Madari S, Walker A, Paiva A, Li Y, Herbst J, Shou W, Weller H. 2019. Addition of optimized bovine serum albumin level in a high-throughput Caco-2 assay enabled accurate permeability assessment for lipophilic compounds. SLAS Discov. 24(7):738–744.
  • Camenisch G, Umehara K. 2012. Predicting human hepatic clearance from in vitro drug metabolism and transport data: a scientific and pharmaceutical perspective for assessing drug-drug interactions. Biopharm Drug Dispos. 33(4):179–194.
  • Carpentier V, Midoux P, Monsigny M, Roche AC. 1993. Endocytosis of α1-acid glycoprotein variants by human monocytic lineage cells. Biol Cell. 77(2):187–193.
  • Ceciliani F, Pocacqua V. 2007. The acute phase protein alpha1-acid glycoprotein: a model for altered glycosylation during diseases. Curr Protein Pept Sci. 8(1):91–108.
  • Chang JH, Chen YC, Cheong J, Jones RS, Pang J. 2019. Investigating the impact of albumin on the liver uptake of pitavastatin and warfarin in nagase analbuminemic rats. Drug Metab Dispos. 47(11):1307–1313.
  • Chaudhury C, Brooks CL, Carter DC, Robinson JM, Anderson CL. 2006. Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry. 45(15):4983–4990.
  • Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL. 2003. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med. 197(3):315–322.
  • Chen C, Zhou H, Guan C, Zhang H, Li Y, Jiang X, Dong Z, Tao Y, Du J, Wang S, et al. 2020. Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: a microdialysis study in rats. Pharmacol Res Perspect. 8(2):e00575.
  • Chen YC, Kenny JR, Wright M, Hop C, Yan Z. 2019. Improving confidence in the determination of free fraction for highly bound drugs using bidirectional equilibrium dialysis. J Pharm Sci. 108(3):1296–1302.
  • Colburn WA. 1982. Albumin does not mediate the removal of taurocholate by the rat liver. J Pharm Sci. 71(3):373–374.
  • Coort SL, Coumans WA, Bonen A, van der Vusse GJ, Glatz JF, Luiken JJ. 2005. Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats. J Lipid Res. 46(6):1295–1302.
  • Cornford EM, Diep CP, Pardridge WM. 1985. Blood-brain barrier transport of valproic acid. J Neurochem. 44(5):1541–1550.
  • D'Hooghe L, Chalmers AD, Heywood S, Whitley P. 2017. Cell surface dynamics and cellular distribution of endogenous FcRn. PLOS One. 12(8):e0182695.
  • 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.
  • DeGoey DA, Chen HJ, Cox PB, Wendt MD. 2018. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J Med Chem. 61(7):2636–2651.
  • Di L. 2021. An update on the importance of plasma protein binding in drug discovery and development. Expert Opin Drug Discov. 16(12):1453–1465.
  • Di L, Breen C, Chambers R, Eckley ST, Fricke R, Ghosh A, Harradine P, Kalvass JC, Ho S, Lee CA, et al. 2017. Industry perspective on contemporary protein-binding methodologies: considerations for regulatory drug-drug interaction and related guidelines on highly bound drugs. J Pharm Sci. 106(12):3442–3452.
  • Diaz-Garcia JM, Evans AM, Rowland M. 1992. Application of the axial dispersion model of hepatic drug elimination to the kinetics of diazepam in the isolated perfused rat liver. J Pharmacokinet Biopharm. 20(2):171–193.
  • DIDB. University of Washington Drug Interaction Database (DIDB), accessed on: … [Fill in with date of extraction of the data/information]; 2022 [accessed 2022 Dec 14].
  • Dolton MJ, Chiang PC, Ma F, Jin JY, Chen Y. 2020. A physiologically based pharmacokinetic model of Vismodegib: deconvoluting the impact of saturable plasma protein binding, pH-dependent solubility and nonsink permeation. AAPS J. 22(5):117.
  • Dubey RK, McAllister CB, Inoue M, Wilkinson GR. 1989. Plasma binding and transport of diazepam across the blood-brain barrier: no evidence for in vivo enhanced dissociation. J Clin Invest. 84(4):1155–1159.
  • Egashira Y, Shimada T, Mayumi K. 2021. A novel experimental and theoretical method for estimating albumin-mediated hepatic uptake based on the albumin binding fraction in plasma and human PK prediction using a physiologically-based pharmacokinetic approach. J Pharm Sci. 110(5):2262–2273.
  • Fasano M, Curry S, Terreno E, Galliano M, Fanali G, Narciso P, Notari S, Ascenzi P. 2005. The extraordinary ligand binding properties of human serum albumin. IUBMB Life. 57(12):787–796.
  • Fernandes CL, Ligabue-Braun R, Verli H. 2015. Structural glycobiology of human alpha1-acid glycoprotein and its implications for pharmacokinetics and inflammation. Glycobiology. 25(10):1125–1133.
  • Fleischer AB, Shurmantine WO, Luxon BA, Forker EL. 1986. Palmitate uptake by hepatocyte monolayers: effect of Albumin Binding. J Clin Invest. 77:964–970.
  • Forker EL, Luxon BA. 1981. Albumin helps mediate removal of taurocholate by rat liver. J Clin Invest. 67:1517–1522.
  • Forker EL, Luxon BA. 1983a. Albumin-mediated transport of Rose Bengal by perfused rat liver. J Clin Invest. 72:1764–1771.
  • Forker EL, Luxon BA. 1983b. Albumin binding and hepatic uptake: the importance of model selection. J Pharm Sci. 72(10):1232–1233.
  • Forker EL, Luxon BA. 1985. Effects of unstirred Disse fluid, nonequilibrium binding, and surface-mediated dissociation on hepatic removal of albumin-bound organic anions. Am J Physiol. 248(11):G709–G717.
  • Forker EL, Luxon BA, Sharma VS. 1985. Hepatic transport and binding of Rose Bengal in the presence of albumin and gamma globulin. Am J Physiol Gastrointest Liver Physiol. 248(6):G702–G708.
  • Forker EL, Luxon BA, Snell M, Shurmantine WO. 1982. Effect of albumin binding on the hepatic transport of Rose Bengal: surface-mediated dissociation of limited capacity. JPET. 223(2):342–347.
  • Foy BD, Toxopeus C, Frazier JM. 1999. Kinetic modeling of slow dissociation of bromosulphophthalein from albumin in perfused rat liver: toxicological implications. Toxicol Sci. 50(1):20–29.
  • Francis LJ, Houston JB, Hallifax D. 2021. Impact of plasma protein binding in drug clearance prediction: a data base analysis of published studies and implications for in vitro-in vivo extrapolation. Drug Metab Dispos. 49(3):188–201.
  • Frostell-Karlsson A, Remaeus A, Roos H, Andersson K, Borg P, Hämäläinen M, Karlsson R. 2000. Biosensor analysis of the interaction between immobilized human serum albumin and drug compounds for prediction of human serum albumin binding levels. J Med Chem. 43:1986–1992.
  • Fujino R, Hashizume K, Aoyama S, Maeda K, Ito K, Toshimoto K, Lee W, Ninomiya SI, Sugiyama Y. 2018. Strategies to improve the prediction accuracy of hepatic intrinsic clearance of three antidiabetic drugs: application of the extended clearance concept and consideration of the effect of albumin on CYP2C metabolism and OATP1B-mediated hepatic uptake. Eur J Pharm Sci. 125:181–192.
  • Fukuchi Y, Toshimoto K, Mori T, Kakimoto K, Tobe Y, Sawada T, Asaumi R, Iwata T, Hashimoto Y, Nunoya KI, 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.
  • Fuse E, Hashimoto A, Sato N, Tanii H, Kuwabara T, Kobayashi S, Sugiyama Y. 2000. Physiological modeling of altered pharmacokinetics of a novel anticancer drug, UCN-01 (7-hydroxystaurosporine), caused by slow dissociation of UCN-01 from human alpha1-acid glycoprotein. Pharm Res. 17(5):553–564.
  • Fuse E, Kuwabara T, Sparreboom A, Sausville EA, Figg WD. 2005. Review of UCN-01 development: a lesson in the importance of clinical pharmacology. J Clin Pharmacol. 45(4):394–403.
  • Gaddum JH. 1937. The quantitative effects of antagonistic drugs. J Physiol. 89:7–9.
  • Gardill BR, Vogl MR, Lin HY, Hammond GL, Muller YA. 2012. Corticosteroid-binding globulin: structure-function implications from species differences. PLOS One. 7(12):e52759.
  • Gerskowitch VP, Hodge J, Hull RA, Shankley NP, Kalindjian SB, McEwen J, Black JW. 2007. Unexpected relationship between plasma protein binding and the pharmacodynamics of 2-NAP, a CCK1-receptor antagonist. Br J Clin Pharmacol. 63(5):618–622.
  • Giannetti AM, Wong H, Dijkgraaf GJ, Dueber EC, Ortwine DF, Bravo BJ, Gould SE, Plise EG, Lum BL, Malhi V, et al. 2011. Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449). J Med Chem. 54(8):2592–2601.
  • Gibson CR, Gleason A, Messina E. 2021. Measurement of total liver blood flow in intact anesthetized rats using ultrasound imaging. Pharmacol Res Perspect. 9(2):e00731.
  • Graham RA, Hop CE, Borin MT, Lum BL, Colburn D, Chang I, Shin YG, Malhi V, Low JA, Dresser MJ. 2012. Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects. Br J Clin Pharmacol. 74(5):788–796.
  • 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.
  • 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.
  • Hammarlund-Udenaes M. 2010. Active-site concentrations of chemicals – are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol. 106(3):215–220.
  • Hassan R, Friebel A, Brackhagen L, Hobloss Z, Myllys M, Gonzalez D, Albrecht W, Mohammed ESI, Seddek AL, Marchan R, et al. 2022. Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity. Arch Toxicol. 96(11):2967–2981.
  • Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W. 2015. Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and alpha-fetoprotein. Toxicol Sci. 143(2):333–348.
  • Horie T, Mizuma T, Kasai S, Awazu S. 1988. Conformational change in plasma albumin due to interaction with isolated rat hepatocyte. Am J Physiol. 254(4 Pt 1):G465–G470.
  • Hsu SH, Cheng AC, Chang TY, Pao LH, Hsiong CH, Wang HJ. 2021. Precisely adjusting the hepatic clearance of highly extracted drugs using the modified well-stirred model. Biomed Pharmacother. 141:111855.
  • Ichikawa M, Tsao SC, Lin TH, Miyauchi S, Sawada Y, Iga T, Hanano M, Sugiyama Y. 1992. Albumin-mediated transport phenomenon’ observed for ligands with high membrane permeability: effect of the unstirred water layer in the Disse’s space of rat liver. J Hepatol. 16:38–49.
  • Imai S, Arai T, Yamada T, Niwa M. 2020. Improved in vitro-in vivo correlation by using the unbound-fraction-adjusted IC50 for breast cancer resistance protein inhibition. Pharm Res. 37(12):230.
  • Inoue M, Hirata E, Morino Y, Nagase S, Chowdhury JR, Chowdhury NR, Arias IM. 1985. The role of albumin in the hepatic transport of bilirubin: studies in mutant analbuminemic rats. J Biochem. 97:737–743.
  • Inoue M, Okajima K, Nagase S, Morino Y. 1983. Plasma clearance of sulfobromophthalein and its interaction with hepatic binding proteins in normal and analbuminemic rats: is plasma albumin essential for vectorial transport of organic anions in the liver? Proc Natl Acad Sci USA. 80(24):7654–7658.
  • Izumi S, Nozaki Y, Komori T, Maeda K, Takenaka O, Kusano K, Yoshimura T, Kusuhara H, Sugiyama Y. 2013. Substrate-dependent inhibition of organic anion transporting polypeptide 1B1: comparative analysis with prototypical probe substrates estradiol-17beta-glucuronide, estrone-3-sulfate, and sulfobromophthalein. Drug Metab Dispos. 41(10):1859–1866.
  • Jones DB, Ching MS, Sr A, Morgan DJ. 1985. A carrier-protein receptor is not a prerequisite for avid hepatic elimination of highly bound compounds: a study of propranolol elimination by the isolated perfused rat liver. Hepatology. 5(4):590–593.
  • Jones DR, Hall SD, Jackson EK, Branch RA, Wilinson GR. 1988. Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding. JPET. 245(3):816–822.
  • Jones RS, Leung C, Chang JH, Brown S, Liu N, Yan Z, Kenny JR, Broccatelli F. 2022. Application of empirical scalars to enable early prediction of human hepatic clearance using IVIVE in drug discovery: an evaluation of 173 drugs. Drug Metab Dispos. 50(8):1053–1063.
  • Jusko WJ, Li X. 2021. Assessment of the Kochak-Benet equation for hepatic clearance for the parallel-tube model: relevance of classic clearance concepts in PK and PBPK. AAPS J. 24(1):5.
  • Jusko WJ, Molins EAG, Ayyar VS. 2020. Seeking nonspecific binding: assessing the reliability of tissue dilutions for calculating fraction unbound. Drug Metab Dispos. 48(10):894–902.
  • Kalvass JC, Phipps C, Jenkins GJ, Stuart P, Zhang X, Heinle L, Nijsen M, Fischer V. 2018. Mathematical and experimental validation of flux dialysis method: an improved approach to measure unbound fraction for compounds with high protein binding and other challenging properties. Drug Metab Dispos. 46(4):458–469.
  • Kameyama T, Sodhi JK, Benet LZ. 2022. Does addition of protein to hepatocyte or microsomal in vitro incubations provide a useful improvement in in vitro-in vivo extrapolation predictability? Drug Metab Dispos. 50(4):401–412.
  • Kaur U, Meng H, Lui F, Ma R, Ogburn RN, Johnson JHR, Fitzgerald MC, Jones LM. 2018. Proteome-wide structural biology: an emerging field for the structural analysis of proteins on the proteomic scale. J Proteome Res. 17(11):3614–3627.
  • Kikuchi R, Peterkin VC, Chiou WJ, de Morais SM, Bow DAJ. 2017. Validation of a total IC50 method which enables in vitro assessment of transporter inhibition under semi-physiological conditions. Xenobiotica. 47(9):825–832.
  • Kilford PJ, Gertz M, Houston JB, Galetin A. 2008. Hepatocellular binding of drugs: correction for unbound fraction in hepatocyte incubations using microsomal binding or drug lipophilicity data. Drug Metab Dispos. 36(7):1194–1197.
  • Kim SJ, Lee KR, 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.
  • Kindla J, Muller F, Mieth M, Fromm MF, Konig J. 2011. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab Dispos. 39(6):1047–1053.
  • Koch-Weser J, Sellers EM. 1976a. Binding of drugs to serum albumin (first of two parts). N Engl J Med. 294(6):311–316.
  • Koch-Weser J, Sellers EM. 1976b. Binding of drugs to serum albumin: second of two parts. N Engl J Med. 294(10):526–531.
  • Kochansky CJ, McMasters DR, Lu P, Koeplinger KA, Kerr HH, Shou M, Korzekwa KR. 2008. Impact of pH on plasma protein binding in equilibrium dialysis. Mol Pharmaceutics. 5(3):438–448.
  • Komori H, Nishi K, Uehara N, Watanabe H, Shuto T, Suenaga A, Maruyama T, Otagiri M. 2012. Characterization of hepatic cellular uptake of alpha1-acid glycoprotein (AGP), part 2: involvement of hemoglobin beta-chain on plasma membranes in the uptake of human AGP by liver parenchymal cells. J Pharm Sci. 101(4):1607–1615.
  • Krause S, Goss KU. 2018. The impact of desorption kinetics from albumin on hepatic extraction efficiency and hepatic clearance: a model study. Arch Toxicol. 92(7):2175–2182.
  • Ladinsky MS, Araujo LP, Zhang X, Veltri J, Galan-Diez M, Soualhi S, Lee C, Irie K, Pinker EY, Narushima S, et al. 2019. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science. 363(6431):eaat4042.
  • Lakeram M, Lockley DJ, Pendlington R, Forbes B. 2008. Optimisation of the caco-2 permeability assay using experimental design methodology. Pharm Res. 25(7):1544–1551.
  • Leung C, Kenny JR, Hop C, Yan Z. 2020. Strategy for determining the free fraction of labile covalent modulators in plasma using equilibrium dialysis. J Pharm Sci. 109(10):3181–3189.
  • Leuthold S, Hagenbuch B, Mohebbi N, Wagner CA, Meier PJ, Stieger B. 2009. Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters. Am J Physiol Cell Physiol. 296(3):C570–C582.
  • Li N, Badrinarayanan A, Ishida K, Li X, Roberts J, Wang S, Hayashi M, Gupta A. 2021. 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.
  • 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.
  • Li P, Fan Y, Wang Y, Lu Y, Yin Z. 2015. Characterization of plasma protein binding dissociation with online SPE-HPLC. Sci Rep. 5:14866.
  • 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.
  • Lin L, Wright MR, Hop C, Wong H. 2022. Physiologically based pharmacokinetic models can be used to predict the unique nonlinear absorption profiles of vismodegib. Drug Metab Dispos. 50(9):1170–1181.
  • Lombardo F, Berellini G, Obach RS. 2018. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 1352 drug compounds. Drug Metab Dispos. 46(11):1466–1477.
  • Loryan I, Reichel A, Feng B, Bundgaard C, Shaffer C, Kalvass C, Bednarczyk D, Morrison D, Lesuisse D, Hoppe E, et al. 2022. Unbound brain-to-plasma partition coefficient, Kp,uu,brain-a game changing parameter for CNS drug discovery and development. Pharm Res. 39(7):1321–1341.
  • Loun B, Hage DS. 1996. Chiral separation mechanisms in protein-based HPLC columns. 2. Kinetic studies of (R)- and (S)-warfarin binding to immobilized human serum albumin. Anal Chem. 68:1218–1225.
  • Luiken JJFP, Turcotte LP, Bonen A. 1999. Protein-mediated palmitate uptake and expression of fatty acid transport proteins in heart giant vesicles. J Lipid Res. 40(6):1007–1016.
  • Mandula H, Parepally JM, Feng R, Smith QR. 2006. Role of site-specific binding to plasma albumin in drug availability to brain. J Pharmacol Exp Ther. 317(2):667–675.
  • Margulis M, Sorota S, Chu I, Soares A, Priestley T, Nomeir AA. 2010. Protein binding-dependent decreases in hERG channel blocker potency assessed by whole-cell voltage clamp in serum. J Cardiovasc Pharmacol. 55(4):368–376.
  • Maruyama T, Otagiri M, Takadate A. 1990. Characterization of drug binding sites on a1-acid glycoprotein. Chem Pharm Bull. 38(6):1688–1691.
  • Masereeuw R, Moons MM, Russel FGM. 1996. Renal excretion and accumulation kinetics of 2-methylbenzoylglycine in the isolated perfused rat kidney. J Pharm Pharmacol. 48:560–565.
  • Matsumoto K, Nishi K, Kikuchi M, Watanabe H, Nakajou K, Komori H, Kadowaki D, Suenaga A, Maruyama T, Otagiri M. 2010. Receptor-mediated uptake of human alpha1-acid glycoprotein into liver parenchymal cells in mice. Drug Metab Pharmacokinet. 25(1):101–107.
  • Matsunaga N, Ufuk A, Morse BL, Bedwell DW, Bao J, Mohutsky MA, Hillgren KM, Hall SD, Houston JB, Galetin A. 2019. Hepatic organic anion transporting polypeptide-mediated clearance in the Beagle Dog: assessing in vitro-in vivo relationships and applying cross-species empirical scaling factors to improve prediction of human clearance. Drug Metab Dispos. 47(3):215–226.
  • Matsuo K, Kumashiro M, Gekko K. 2020. Characterization of the mechanism of interaction between alpha1-acid glycoprotein and lipid membranes by vacuum-ultraviolet circular-dichroism spectroscopy. Chirality. 32(5):594–604.
  • Matsuo K, Namatame H, Taniguchi M, Gekko K. 2009. Membrane-induced conformational change of alpha1-acid glycoprotein characterized by vacuum-ultraviolet circular dichroism spectroscopy. Biochemistry. 48(38):9103–9111.
  • Matsusaka K, Ishima Y, Maeda H, Kinoshita R, Ichimizu S, Taguchi K, Giam Chuang VT, Nishi K, Yamasaki K, Otagiri M, et al. 2019. Alpha1-acid glycoprotein has the potential to serve as a biomimetic drug delivery carrier for anticancer agents. J Pharm Sci. 108(11):3592–3598.
  • McDade JR, Naylor MT, Michele DE. 2021. Sarcolemma wounding activates dynamin-dependent endocytosis in striated muscle. FEBS J. 288(1):160–174.
  • McLure JA, Miners JO, Birkett DJ. 2000. Nonspecific binding of drugs to human liver microsomes. J Clin Pharmacol. 49(5):453–461.
  • Menochet K, Kenworthy KE, Houston JB, Galetin A. 2012. Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model. J Pharmacol Exp Ther. 341(1):2–15.
  • Michaelis L, Menten ML. 1913. Die Kinetik der Invertinwirkung. Biochem Z. 49:333–369.
  • Michaelis L, Menten ML, Johnson KA, Goody RS. 2011. The original Michaelis constant: translation of the 1913 Michaelis-Menten paper. Biochemistry. 50(39):8264–8269.
  • Miller RR, Madeira M, Wood HB, Geissler WM, Raab CE, Martin IJ. 2020. Integrating the impact of lipophilicity on potency and pharmacokinetic parameters enables the use of diverse chemical space during small molecule drug optimization. J Med Chem. 63(21):12156–12170.
  • Miyauchi S, Kim SJ, Lee W, Sugiyama Y. 2022. Consideration of albumin-mediated hepatic uptake for highly protein-bound anionic drugs: bridging the gap of hepatic uptake clearance between in vitro and in vivo. Pharmacol Ther. 229:107938.
  • Miyauchi S, Masuda M, Kim SJ, Tanaka Y, Lee KR, 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.
  • Morita T, Akiyoshi T, Sato R, Katayama K, Yajima K, Kataoka H, Imaoka A, Sugimoto Y, Ohtani H. 2020. pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2. Drug Metab Pharmacokinet. 35(2):220–227.
  • Morris ME, Rodriguez-Cruz V, Felmlee MA. 2017. SLC and ABC transporters: expression, localization, and species differences at the blood-brain and the blood-cerebrospinal fluid barriers. AAPS J. 19(5):1317–1331.
  • Nagase S, Shimamune K, Shumiya S. 1979. Albumin-deficient rat mutant. Science. 205(4406):590–591.
  • Nakai D, Kumamoto K, Sakikawa C, Kosaka T, Tokui T. 2004. Evaluation of the protein binding ratio of drugs by a micro-scale ultracentrifugation method. J Pharm Sci. 93(4):847–854.
  • Naruhashi K, Tamai I, Li Q, Sai Y, Tsuji A. 2003. Experimental demonstration of the unstirred water layer effect on drug transport in Caco-2 cells. J Pharm Sci. 92(7):1502–1508.
  • Nation RL, Theuretzbacher U, Tsuji BT. 2018. Concentration-dependent plasma protein binding: expect the unexpected. Eur J Pharm Sci. 122:341–346.
  • Naylor MR, Ly AM, Handford MJ, Ramos DP, Pye CR, Furukawa A, Klein VG, Noland RP, Edmondson Q, Turmon AC, et al. 2018. Lipophilic permeability efficiency reconciles the opposing roles of lipophilicity in membrane permeability and aqueous solubility. J Med Chem. 61(24):11169–11182.
  • Nelson CH, Peng CC, Lutz JD, Yeung CK, Zelter A, Isoherranen N. 2016. Direct protein-protein interactions and substrate channeling between cellular retinoic acid binding proteins and CYP26B1. FEBS Lett. 590(16):2527–2535.
  • Nishi K, Komine Y, Fukunaga N, Maruyama T, Suenaga A, Otagiri M. 2006. Involvement of disulfide bonds and histidine 172 in a unique beta-sheet to alpha-helix transition of alpha 1-acid glycoprotein at the biomembrane interface. Proteins. 63(3):611–620.
  • Nishi K, Maruyama T, Halsall HB, Handa T, Otagiri M. 2004. Binding of a1-acid glycoprotein to membrane results in a unique structural change and ligand release. Biochemistry. 43:10513–10519.
  • Nishi K, Sakai N, Komine Y, Maruyama T, Halsall HB, Otagiri M. 2002. Structural and drug-binding properties of a1-acid glycoprotein in reverse micelles. Biochim Biophys Acta. 1601:185–191.
  • O'Connell MB. 1995. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol. 35(9S):18S–124.
  • Obach RS. 1996. The importance of nonspecific binding in in vitro matrices, its impact on enzyme kinetic studies of drug metabolism reactions, and implications for in vitro-in vivo correlations. DMD. 24(10):1047–1049.
  • Obach RS. 1997. Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to heaptic clearance as assessed through examination of warfarin, imipramine, and propranolol. Drug Metab Dispos. 25(12):1359–1369.
  • Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, Wastall P. 1997. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. JPET. 283(1):46–58.
  • Oie S, Fiori F. 1985. Effects of albumin and alpha-i acid glycoprotein on elimination of prazosin and antipyrine in the isolated perfused rat liver. JPET. 234(3):636–640.
  • Olsen H, Andersen A, Nordbo A, Kongsgaard UE, Bormer OP. 2004. Pharmaceutical-grade albumin: impaired drug-binding capacity in vitro. BMC Clin Pharmacol. 4(4):1–9. DOI: 10.1186/1472-6904-4-4
  • Otagiri M. 2005. A molecular functional study on the interactions of drugs with plasma proteins. Drug Metab Pharmacokinet. 20(5):309–323.
  • 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.
  • Pang KS, Rowland M. 1977a. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokinet Biopharm. 5(6):625–653.
  • Pang KS, Rowland M. 1977b. Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused rat liver in situ preparation. J Pharmacokinet Biopharm. 5(6):655–680.
  • Pardridge WM. 2001. Brain drug targeting and gene technologies. Jpn J Pharmacol. 87(2):97–103.
  • Pardridge WM, Landaw EM. 1984. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands: empiric testing of the free hormone hypothesis. J Clin Invest. 74(3):745–752.
  • Pardridge WM, Sakiyama R, Frierer G. 1982. Transport of propranolol and lidocaine through the rat blood-brain barrier: primary role of globulin-bound drug. J Clin Invest. 71:900–908.
  • Pardridge WM, Van Herle AJ, Naruse RT, Fierer G, Costin A. 1983. In vivo quantification of receptor-mediated uptake of asialoglycoproteins by rat liver. J Biol Chem. 258(2):990–994.
  • Park SA, Choe YH, Lee SH, Hyun YM. 2018. Two-photon intravital imaging of leukocytes during the immune response in lipopolysaccharide-treated mouse liver. J Vis Exp. (132):57191. DOI:10.3791/57191
  • Patilea-Vrana G, Unadkat JD. 2016. Transport vs. metabolism: what determines the pharmacokinetics and pharmacodynamics of drugs? Insights from the extended clearance model. Clin Pharmacol Ther. 100(5):413–418.
  • Peyret T, Poulin P, Krishnan K. 2010. A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals. Toxicol Appl Pharmacol. 249(3):197–207.
  • Piazza I, Kochanowski K, Cappelletti V, Fuhrer T, Noor E, Sauer U, Picotti P. 2018. A map of protein-metabolite interactions reveals principles of chemical communication. Cell. 172(1–2):358–372.e323.
  • Pimpaneau V, Midoux P, Durand GD, Baetselier P, Monsigny M, Roche AC. 1989. Endocytosis of α1-acid glycoprotein variants and of neoglycoproteins containing mannose derivatives by a mouse hybridoma cell line (2C11–12). Comparison with mouse peritoneal macrophages. Glycoconjugate J. 6(4):561–574.
  • Poulin P. 2015. A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design. J Pharm Sci. 104(7):2359–2368.
  • Poulin P, Bteich M, Haddad S. 2017. Supplemental analysis of the prediction of hepatic clearance of binary mixtures of bisphenol A and naproxen determined in an isolated perfused rat liver model to promote the understanding of potential albumin-facilitated hepatic uptake mechanism. J Pharm Sci. 106(11):3207–3214.
  • Poulin P, Haddad S. 2015. Albumin and uptake of drugs in cells: additional validation exercises of a recently published equation that quantifies the albumin-facilitated uptake mechanism(s) in physiologically based pharmacokinetic and pharmacodynamic modeling research. J Pharm Sci. 104(12):4448–4458.
  • Poulin P, Haddad S. 2018. Extrapolation of the hepatic clearance of drugs in the absence of albumin in vitro to that in the presence of albumin in vivo: comparative assessement of 2 extrapolation models based on the albumin-mediated hepatic uptake theory and limitations and mechanistic insights. J Pharm Sci. 107(7):1791–1797.
  • Poulin P, Haddad S. 2021. A new guidance for the prediction of hepatic clearance in the early drug discovery and development from the in vitro-to-in vivo extrapolation method and an approach for exploring whether an albumin-mediated hepatic uptake phenomenon could be present under in vivo conditions. J Pharm Sci. 110(7):2841–2858.
  • 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.
  • 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.
  • Predescue D, Predescue S, McQuistan T, Palade GE. 1998. Transcytosis of a1-acidic glycoprotein in the continuous microvascular endothelium. Proc Natl Acad Sci USA. 95(11):6175–6180.
  • Pyzik M, Rath T, Kuo TT, Win S, Baker K, Hubbard JJ, Grenha R, Gandhi A, Kramer TD, Mezo AR, et al. 2017. Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury. Proc Natl Acad Sci USA. 114(14):E2862–E2871.
  • Qin L, Crawford JM. 2018. Anatomy and cellular functions of the liver. In: Arun J, Sanyal TDB, Lindor KD, Terrault NA, editors. Zakim and Boyer’s hepatology. 7th ed. Amsterdam: Elsevier; p. 2–19.e14.
  • Rathbone T, Ates I, Fernando L, Addlestone E, Lee CM, Richards VP, Cottle RN. 2022. Electroporation-mediated delivery of Cas9 ribonucleoproteins results in high levels of gene editing in primary hepatocytes. Crispr J. 5(3):397–409.
  • Reijenga J, van Hoof A, van Loon A, Teunissen B. 2013. Development of methods for the determination of pKa values. Anal Chem Insights. 8:53–71.
  • Riccardi K, Cawley S, Yates PD, Chang C, Funk C, Niosi M, Lin J, Di L. 2015. Plasma protein binding of challenging compounds. J Pharm Sci. 104(8):2627–2636.
  • 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.
  • Rich RL, Day YS, Morton TA, Myszka DG. 2001. High-resolution and high-throughput protocols for measuring drug/human serum albumin interactions using BIACORE. Anal Biochem. 296(2):197–207.
  • 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.
  • Roberts MS, Rowland M. 1986. A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations. J Pharmacokinet Biopharm. 14(3):227–260.
  • Roll GR, Willenbring H. 2010. Transplanted nonviable human hepatocytes produce appreciable serum albumin levels in mice. Stem Cell Res. 5(3):267–270.
  • Rosenthal SM, White EC. 1924. Studies in hepatic function. VI A. The pharmacological behavior of certain phthalein dyes B. The value of selected phthalein compounds in the estimation of hepatic function. J Pharmacol Exp Ther. 24(4):265–288.
  • Ross HA. 1978. A dialysis rate method for the measurement of free iodothyronine and steroid hormones in blood. Experientia. 34(4):538–539.
  • Rougee LRA, Mohutsky MA, Bedwell DW, Ruterbories KJ, Hall SD. 2016. The impact of the hepatocyte-to-plasma pH gradient on the prediction of hepatic clearance and drug-drug interactions for CYP2D6 substrates. Drug Metab Dispos. 44(11):1819–1827.
  • Rougee LRA, Mohutsky MA, Bedwell DW, Ruterbories KJ, Hall SD. 2017. The impact of the hepatocyte-to-plasma pH gradient on the prediction of hepatic clearance and drug-drug interactions for CYP2C9 and CYP3A4 substrates. Drug Metab Dispos. 45(9):1008–1018.
  • Rowland M, Roberts MS, Pang KS. 2021. In defense of current concepts and applications of clearance in drug development and therapeutics. Drug Metab Dispos. 50(2):187–190.
  • Rowley M, Kulagowski JJ, Watt AP, Rathbone D, Stevenson GI, Carling RW, Baker R, Marshall GR, Kemp JA, Foster AC, et al. 1997. Effect of plasma protein binding on in vivo activity and brain penetration of glycine/NMDA receptor antagonists. J Med Chem. 40(25):4053–4068.
  • Russi M, Cavalieri G, Marson D, Laurini E, Pricl S. 2022. Binding of the B-Raf inhibitors dabrafenib and vemurafenib to human serum albumin: a biophysical and molecular simulation study. Mol Pharm. 19(5):1619–1634.
  • Ryu S, Riccardi K, Patel R, Zueva L, Burchett W, Di L. 2019. Applying two orthogonal methods to assess accuracy of plasma protein binding measurements for highly bound compounds. J Pharm Sci. 108(11):3745–3749.
  • Ryu S, Tess D, Chang G, Keefer C, Burchett W, Steeno GS, Novak JJ, Patel R, Atkinson K, Riccardi K, et al. 2020. Evaluation of fraction unbound across 7 tissues of 5 species. J Pharm Sci. 109(2):1178–1190.
  • Ryu S, Tess D, Di L. 2022. Addressing the accuracy of plasma protein binding measurement for highly bound compounds using the dilution method. AAPS J. 25(1):7.
  • Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT. 2014. Unraveling the interaction between FcRn and albumin: opportunities for design of albumin-based therapeutics. Front Immunol. 5:682.
  • Sato R, Akiyoshi T, Morita T, Katayama K, Yajima K, Kataoka H, Imaoka A, Ohtani H. 2021. Dual kinetics of OATP2B1: inhibitory potency and pH-dependence of OATP2B1 inhibitors. Drug Metab Pharmacokinet. 41:100416.
  • Schafer-Korting M, Korting HC, Rittler W, Obermuller W. 1995. Influence of serum protein binding on the in vitro activity of anti-fungal agents. Infection. 23(5):292–297.
  • Scharschmidt BF, Lake JR, Renner EL, Licko V, Van Dyke RW. 1986. Fluid phase endocytosis by cultured rat hepatocytes and perfused rat liver: implications for plasma membrane turnover and vesicular trafficking of fluid phase markers. Proc Natl Acad Sci USA. 83(24):9488–9492.
  • Schmidt MM, Townson SA, Andreucci AJ, King BM, Schirmer EB, Murillo AJ, Dombrowski C, Tisdale AW, Lowden PA, Masci AL, et al. 2013. Crystal structure of an HSA/FcRn complex reveals recycling by competitive mimicry of HSA ligands at a pH-dependent hydrophobic interface. Structure. 21(11):1966–1978.
  • Sevillano D, Gimenez MJ, Alou L, Aguilar L, Cafini F, Torrico M, Gonzalez N, Echeverria O, Coronel P, Prieto J. 2007. Effects of human albumin and serum on the in vitro bactericidal activity of cefditoren against penicillin-resistant Streptococcus pneumoniae. J Antimicrob Chemother. 60(1):156–158.
  • Seyfinejad B, Ozkan SA, Jouyban A. 2021. Recent advances in the determination of unbound concentration and plasma protein binding of drugs: analytical methods. Talanta. 225:122052.
  • Simmonds B, Wang CW, Kapoor R. 2010. Real-time association rate constant measurement using combination tapered fiber-optic biosensor (CTFOB) dip-probes. Proc SPIE Int Soc Opt Eng. 7559:75590Q75591–75590Q75595.
  • Smith DA, Di L, Kerns EH. 2010. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 9(12):929–939.
  • Smith SA, Waters NJ. 2018. Pharmacokinetic and pharmacodynamic considerations for drugs binding to alpha-1-acid glycoprotein. Pharm Res. 36(2):30.
  • Sparreboom A, Chen H, Acharya MR, Senderowicz AM, Messmann RA, Kuwabara T, Venzon DJ, Murgo AJ, Headlee D, Sausville EA, et al. 2004. Effects of alpha1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine. Clin Cancer Res. 10(20):6840–6846.
  • Srinivasan B. 2021. A guide to the Michaelis-Menten equation: steady state and beyond. FEBS J. 289(20):6086–6098.
  • Stegmayr BG. 2015. New insight in impaired binding capacity for albumin in uraemic patients. Acta Physiol. 215(1):5–8.
  • Stremmel W, Potter BJ, Berk PD. 1983. Studies of albumin binding to rat liver plasma membranes. Implications for the albumin receptor hypothesis. Biochim Biophys Acta. 5756(1):20–27.
  • Summerfield SG, Yates JWT, Fairman DA. 2022. Free drug theory – no longer just a hypothesis? Pharm Res. 39(2):213–222.
  • Svenson A, Holmer E, Andersson L-O. 1974. A new method for the measurement of dissociation rates for complexes between small ligands and proteins as applied to the palmitate and bilirubin complexes with serum albumin. Biochim Biophys Acta. 342(1):54–59.
  • Taguchi K, Nishi K, Giam Chuang VT, Maruyama T, Otagiri M. 2013. Chapter 6, molecular aspects of human alpha-1 acid glycoprotein—structure and function. Acute Phase Proteins. p. 139–162.
  • Tess DA, Ryu S, Di L. 2022. In vitro – in vivo extrapolation of hepatic clearance in preclinical species. Pharm Res. 39(7):1615–1632.
  • Tillement JP, Urien S, Chaumet-Riffaud P, Riant P, Bree F, Morin D, Albengres E, Barre J. 1988. Blood binding and tissue uptake of drugs. Recent advances and perspectives. Fundam Clin Pharmacol. 2(3):223–238.
  • Trimble ME. 1990. Renal palmitate transport: possible sites for interaction with a plasma membrane fatty acid-binding protein. Mol Cell Biochem. 98:201–207.
  • Trimble ME. 1993. Palmitate transport by rat renal basolateral membrane vesicles in the presence of albumin. J Am Soc Nephrol. 3:1920–1929.
  • 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 Biopharm. 16(2):165–181.
  • Tsao SC, Sugiyama Y, Sawada Y, Nagase S, Iga T, Hanano M. 1986. Effect of albumin on hepatic uptake of warfarin in normal and analbuminemic mutant rats: analysis by multiple indicator dilution method. J Pharmacokinet Biopharm. 14(1):51–64.
  • Tsao SC, Sugiyama Y, Shinmura K, Sawada Y, Nagase S, Iga T, Hanano M. 1988. Protein-mediated heptaic uptake of rose bengal in analbuminemic mutant rats (NAR). DMD. 16(3):482–489.
  • Ukairo O, Kanchagar C, Moore A, Shi J, Gaffney J, Aoyama S, Rose K, Krzyzewski S, McGeehan J, Andersen ME, et al. 2013. Long-term stability of primary rat hepatocytes in micropatterned cocultures. J Biochem Mol Toxicol. 27(3):204–212.
  • van der Made TK, Fedecostante M, Scotcher D, Rostami-Hodjegan A, Sastre Torano J, Middel I, Koster AS, Gerritsen KG, Jankowski V, Jankowski J, et al. 2019. Quantitative translation of microfluidic transporter in vitro data to in vivo reveals impaired albumin-facilitated indoxyl sulfate secretion in chronic kidney disease. Mol Pharm. 16(11):4551–4562.
  • Van der Sluijs P, Postema B, Meijer DKF. 1987. Lactosylation of albumin reduces uptake rate of dibromosulfophthalein in perfused rat liver and dissociation rate from albumin in vitro. Hepatology. 7(4):688–695.
  • van Steeg TJ. 2008. The ‘free drug hypothesis’: fact or fiction? [Doctor (dr.)]. Leiden: Leiden University.
  • Varma MV, Steyn SJ, Allerton C, El-Kattan AF. 2015. Predicting clearance mechanism in drug discovery: Extended Clearance Classification System (ECCS). Pharm Res. 32(12):3785–3802.
  • Wang H, Zhang R, Bridle KR, Jayachandran A, Thomas JA, Zhang W, Yuan J, Xu ZP, Crawford DH, Liang X, et al. 2017. Two-photon dual imaging platform for in vivo monitoring cellular oxidative stress in liver injury. Sci Rep. 7:45374.
  • Wang HJ, Benet LZ. 2019. Protein binding and hepatic clearance: re-examining the discrimination between models of hepatic clearance with diazepam in the isolated perfused rat liver preparation. Drug Metab Dispos. 47(12):1397–1402.
  • Waters NJ, Obach RS, Di L. 2021. Consideration of the unbound drug concentration in enzyme kinetics. Methods Mol Biol. 2342:113–145.
  • Watkins S, Madison J, Galliano M, Minchiotti L, Putnam FW. 1994. Analbuminemia: three cases resulting from different point mutations in the albumin gene. Proc Natl Acad Sci USA. 91:9417–9421.
  • Weisiger RA. 1985. Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver. Proc Natl Acad Sci USA. 82(5):1563–1567.
  • Weisiger RA, Gollan JL, Ockner RK. 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.
  • Weisiger RA, Zacks CM, Smith ND, Boyer JL. 1984. Effect of albumin binding on extraction of sulfobromophthalein by perfused elasmobranch liver: evidence for dissociation-limited uptake. Hepatology. 4(3):492–501.
  • Whittem T, Ferguson DC. 1990. Kinetics of triiodothyronine dissociation from bovine serum albumin: modification of the resin capture method with subsequent computer modeling. Endocrinology. 127(5):2190–2198.
  • WHO. 2002. Use of anticoagulants in diagnostic laboratory investigations. Switzerland: World Health Organization. Diagnostic Imaging and Laboratory Technology. WHO/DIL/LAB/99.1 Rev.2.
  • Wilting J, Hart BJ, de Gier JJ. 1980. The role of albumin conformation in the binding of diazepam to human serum albumin. Biochim Biophys Acta. 626(2):291–298.
  • Wilting J, van der Giesen WF, Janssen LH, Weideman MM, Otagiri M, Perrin JH. 1980. The effect of albumin conformation on the binding of warfarin to human serum albumin. The dependence of the binding of warfarin to human serum albumin on the hydrogen, calcium, and chloride ion concentrations as studied by circular dichroism, fluorescence, and equilibrium dialysis. J Biol Chem. 255(7):3032–3037.
  • Winiwarter S, Chang G, Desai P, Menzel K, Faller B, Arimoto R, Keefer C, Broccatell F. 2019. Prediction of fraction unbound in microsomal and hepatocyte incubations: a comparison of methods across industry datasets. Mol Pharm. 16(9):4077–4085.
  • Wolf KK, Brouwer KR, Pollack, GM, Brouwer Kl. 2008. Effect of albumin on the biliary clearance of compounds in sandwich-cultured rat hepatocytes. Drug Metab Dispos. 36(10):2086–2092.
  • 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.
  • 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.
  • Yadav JE, Hassani M, Sodhi J, Lauschke VM, Hartman JH, Russell LE. 2021. Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data. Drug Metab Rev. 53(2):207–233.
  • Yang W, Gadgil P, Krishnamurthy VR, Landis M, Mallick P, Patel D, Patel PJ, Reid DL, Sanchez-Felix M. 2020. The evolving druggability and developability space: chemically modified new modalities and emerging small molecules. AAPS J. 22(2):21.
  • Yang W, Zhao H, Dou Y, Wang P, Chang Q, Qiao X, Wang X, Xu C, Zhang Z, Zhang L. 2023. CYP3A4 and CYP3A5 expression is regulated by CYP3A4*1GinCRISPR/Cas9 edited HepG2 cells. Drug Metab Dispos. 51(4):492–498.
  • Yasuhara M, Fujiwara J, Kitade S, Katayama H, Okumura K, Hori R. 1985. Effect of altered plasma protein binding on pharmacokinetics and pharmacodynamics of propranolol in rats after surgery: role of alpha-i-acid glycoprotein. JPET. 235(2):513–520.
  • Yim DS. 2019. Potency and plasma protein binding of drugs in vitro-a potentially misleading pair for predicting in vivo efficacious concentrations in humans. Korean J Physiol Pharmacol. 23(4):231–236.
  • Yin M, Storelli F, Unadkat JD. 2022. Is the protein-mediated uptake of drugs by organic anion transporting polypeptides a real phenomenon or an artifact? Drug Metab Dispos. 50(9):1132–1141.
  • Zeitlinger MA, Sauermann R, Traunmuller F, Georgopoulos A, Muller M, Joukhadar C. 2004. Impact of plasma protein binding on antimicrobial activity using time-killing curves. J Antimicrob Chemother. 54(5):876–880.
  • Zhai XY, Nielsen R, Birn H, Drumm K, Mildenberger S, Freudinger R, Moestrup SK, Verroust PJ, Christensen EI, Gekle M. 2000. Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int. 58(4):1523–1533.
  • Zhang D, Hop C, Patilea-Vrana G, Gampa G, Seneviratne HK, Unadkat JD, Kenny JR, Nagapudi K, Di L, Zhou L, et al. 2019. Drug concentration asymmetry in tissues and plasma for small molecule-related therapeutic modalities. Drug Metab Dispos. 47(10):1122–1135.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.