Advanced search
Publication Cover
Drug Metabolism Reviews Volume 53, 2021 - Issue 3
Submit an article Journal homepage
480
Views
2
CrossRef citations to date
0
Altmetric
Review Articles

Recent advances in drug transporter sciences: highlights from the year 2020

Paresh P. Chothea Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceutical Company Limited, Cambridge, MA, USACorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0001-5661-9011View further author information
ORCID Icon,
Masanori Nakakariyab Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, JapanView further author information
,
Charles J. Rotterc Global Drug Metabolism and Pharmacokinetics, Takeda California Incorporated, San Diego, CA, USAView further author information
,
Philip Sandovala Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceutical Company Limited, Cambridge, MA, USAView further author information
&
Kimio Tohyamaa Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceutical Company Limited, Cambridge, MA, USAView further author information
Pages 321-349 | Received 31 May 2021, Accepted 28 Jul 2021, Published online: 14 Sep 2021

References

  • 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.
  • 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.
  • Jones HM, Barton HA, Lai Y, Bi YA, 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.
  • 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.
  • Menochet K, Kenworthy KE, Houston JB, Galetin A. 2012. 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.
  • Riccardi KA, Tess DA, Lin J, Patel R, Ryu S, Atkinson K, Di L, Li R. 2019. A novel unified approach to predict human hepatic clearance for both enzyme- and transporter-mediated mechanisms using suspended human hepatocytes. Drug Metab Dispos. 47(5):484–492.

References

  • Barnett S, Ogungbenro K, Menochet K, Shen H, Humphreys WG, Galetin A. 2019. Comprehensive evaluation of the utility of 20 endogenous molecules as biomarkers of OATP1B inhibition compared with rosuvastatin and coproporphyrin I. J Pharmacol Exp Ther. 368(1):125–135.
  • Dong Z, Yang X, Arya V, and Zhang L. 2016. Comparing various in vitro prediction criteria to assess the potential of a new molecular entity (NME) to inhibit OCT2 and MATE transporters in vivo. Clin Pharmacol Ther 99(S1):S94.
  • European Medicines Agency (EMA). 2017. Concept paper on a revision of the guideline on the investigation of drug interactions. https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-revision-guideline-investigation-drug-interactions_en.pdf
  • Miyake T, Kimoto E, Luo L, Mathialagan S, Horlbogen LM, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M et al. 2021. Identification of appropriate endogenous biomarker for risk assessment of multidrug and toxin extrusion protein-mediated drug-drug interactions in healthy volunteers. Clin Pharmacol Ther. 109(2):507–516.
  • Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M et al. 2020. Dose-dependent inhibition of OATP1B by rifampicin in healthy volunteers: comprehensive evaluation of candidate biomarkers and OATP1B probe drugs. Clin Pharmacol Ther. 107(4):1004–1013.
  • Neuvonen M, Hirvensalo P, Tornio A, Rago B, West M, Lazzaro S, Mathialagan S, Varma M, Cerny MA, Costales C et al. 2021. Identification of glycochenodeoxycholate 3-O-glucuronide and glycodeoxycholate 3-O-glucuronide as highly sensitive and specific OATP1B1 biomarkers. Clin Pharmacol Ther. 109(3):646–657.
  • Panfen E, Chen W, Zhang Y, Sinz M, Marathe P, Gan J, Shen H. 2019. Enhanced and persistent inhibition of organic cation transporter 1 activity by preincubation of cyclosporine A. Drug Metab Dispos. 47(11):1352–1360.
  • Pharmaceuticals and Medical Devices Agency of Japan (PMDA). 2019. Guideline on drug interaction for drug development and appropriate provision of information. http://www.pmda.go.jp/files/000228122.pdf
  • Shitara Y, Sugiyama Y. 2017. Preincubation-dependent and long-lasting inhibition of organic anion transporting polypeptide (OATP) and its impact on drug-drug interactions. Pharmacol Ther. 177:67–80.
  • U. S. Food and Drug Administration (FDA). 2020. Center for Drug Evaluation and Research, Guidance for Industry; In vitro drug interaction studies – cytochrome P450 enzyme and transporter mediated drug interactions. https://www.fda.gov/media/134582/download

References

  • Kim HI, Raffler J, Lu W, Lee JJ, Abbey D, Saleheen D, Rabinowitz JD, Bennett MJ, Hand NJ, Brown C et al. 2017. Fine mapping and functional analysis reveal a role of SLC22A1 in acylcarnitine transport. Am J Hum Genet. 101(4):489–502.
  • Mathialagan S, Feng B, Rodrigues AD, Varma MVS. 2020. Drug-drug interactions involving renal OCT2/MATE transporters: clinical risk assessment may require endogenous biomarker-informed approach. Clin Pharmacol Ther. DOI:https://doi.org/10.1002/cpt.2089.
  • Matthaei J, Kuron D, Faltraco F, Knoch T, Dos Santos Pereira JN, Abu Abed M, Prukop T, Brockmoller J, Tzvetkov MV. 2016. OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics. Clin Pharmacol Ther. 99(6):633–641.
  • Panfen E, Chen W, Zhang Y, Sinz M, Marathe P, Gan J, Shen H. 2019. Enhanced and persistent inhibition of organic cation transporter 1 activity by preincubation of cyclosporine A. Drug Metab Dispos. 47(11):1352–1360.
  • Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B, Altmaier E, CardioGram , Deloukas P, Erdmann J et al. 2011. Human metabolic individuality in biomedical and pharmaceutical research. Nature. 477(7362):54–60.
  • Zamek-Gliszczynski MJ, Chu X, Cook JA, Custodio JM, Galetin A, Giacomini KM, Lee CA, Paine MF, Ray AS, Ware JA et al. 2018. ITC commentary on metformin clinical drug-drug interaction study design that enables an efficacy- and safety-based dose adjustment decision. Clin Pharmacol Ther. 104(5):781–784.

References

  • Jones NS, Yoshida K, Salphati L, Kenny JR, Durk MR, Chinn LW. 2020. Complex DDI by fenebrutinib and the use of transporter endogenous biomarkers to elucidate the mechanism of DDI. Clin Pharmacol Ther. 107(1):269–277.
  • Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M et al. 2020. Dose-dependent inhibition of OATP1B by rifampicin in healthy volunteers: comprehensive evaluation of candidate biomarkers and OATP1B probe drugs. Clin Pharmacol Ther. 107(4):1004–1013.
  • Neuvonen M, Hirvensalo P, Tornio A, Rago B, West M, Lazzaro S, Mathialagan S, Varma M, Cerny MA, Costales C et al. 2021. Identification of glycochenodeoxycholate 3-O-glucuronide and glycodeoxycholate 3-O-glucuronide as highly sensitive and specific OATP1B1 biomarkers. Clin Pharmacol Ther. 109(3):646–657.

References

  • Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A. 2018. Cytochrome P450 3A induction predicts P-glycoprotein induction; part 1: establishing induction relationships using ascending dose rifampin. Clin Pharmacol Ther. 104(6):1182–1190.
  • Murray M, Zhou F. 2017. Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. Br J Pharmacol. 174(13):1908–1924.
  • Neuhoff S, Yeo KR, Barter Z, Jamei M, Turner DB, Rostami-Hodjegan A. 2013. Application of permeability-limited physiologically-based pharmacokinetic models: part II – prediction of P-glycoprotein mediated drug-drug interactions with digoxin. J Pharm Sci. 102(9):3161–3173.
  • Otsuka Y, Choules MP, Bonate PL, Komatsu K. 2020. Physiologically-based pharmacokinetic modeling for the prediction of a drug-drug interaction of combined effects on P-glycoprotein and cytochrome P450 3A. CPT Pharmacometrics Syst Pharmacol. 9(11):659–669.
  • Rodrigues AD, Lai Y, Shen H, Varma MVS, Rowland A, Oswald S. 2020. Induction of human intestinal and hepatic organic anion transporting polypeptides: where is the evidence for its relevance in drug-drug interactions? Drug Metab Dispos. 48(3):205–216.
  • Yamazaki S, Costales C, Lazzaro S, Eatemadpour S, Kimoto E, Varma MV. 2019. Physiologically-based pharmacokinetic modeling approach to predict rifampin-mediated intestinal P-glycoprotein induction. CPT Pharmacometrics Syst Pharmacol. 8(9):634–642.

References

  • Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R et al. 2005. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 129(2):476–485.
  • Murray M, Zhou F. 2017. Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. Br J Pharmacol. 174(13):1908–1924.
  • Niu C, Wang Y, Zhao X, Tep S, Murakami E, Subramanian R, Smith B, Lai Y. 2019. Organic anion-transporting polypeptide genes are not induced by the pregnane X receptor activator rifampin: studies in hepatocytes in vitro and in monkeys in vivo. Drug Metab Dispos. 47(12):1433–1442.
  • Oscarson M, Zanger UM, Rifki OF, Klein K, Eichelbaum M, Meyer UA. 2006. Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 80(5):440–456.
  • Rodrigues AD, Lai Y, Shen H, Varma MVS, Rowland A, Oswald S. 2020. Induction of human intestinal and hepatic organic anion transporting polypeptides: where is the evidence for its relevance in drug-drug interactions? Drug Metab Dispos. 48(3):205–216.
  • Zhang W, Deng S, Chen XP, Zhou G, Xie HT, He FY, Cao D, Li YJ, Zhou HH. 2008. Pharmacokinetics of rosuvastatin when coadministered with rifampicin in healthy males: a randomized, single-blind, placebo-controlled, crossover study. Clin Ther. 30(7):1283–1289.

References

  • Rodrigues D, Rowland A. 2019. From endogenous compounds as biomarkers to plasma-derived nanovesicles as liquid biopsy; has the golden age of translational pharmacokinetics-absorption, distribution, metabolism, excretion-drug-drug interaction science finally arrived? Clin Pharmacol Ther. 105(6):1407–1420.
  • Rodrigues AD, Rowland A. 2020. Profiling of drug-metabolizing enzymes and transporters in human tissue biopsy samples: a review of the literature. J Pharmacol Exp Ther. 372(3):308–319.
  • Rodrigues AD, van Dyk M, Sorich MJ, Fahmy A, Useckaite Z, Newman LA, Kapetas AJ, Mounzer R, Wood LS, Johnson JG et al. 2021. Exploring the use of serum-derived small extracellular vesicles as liquid biopsy to study the induction of hepatic cytochromes P450 and organic anion transporting polypeptides. Clin Pharmacol Ther. 110(1):248–258.

References

  • Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR et al. 2005. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 115(11):3285–3290.
  • Deo AK, Borson S, Link JM, Domino K, Eary JF, Ke B, Richards TL, Mankoff DA, Minoshima S, O’Sullivan F et al. 2014. Activity of P-glycoprotein, a beta-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease. J Nucl Med. 55(7):1106–1111.
  • Di L, Rong H, Feng B. 2013. {Di, 2013 #83} Miniperspective. J Med Chem. 56(1):2–12.
  • Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. 2010. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 330(6012):1774.

References

  • 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.
  • 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.
  • Nishimura M, Yoshitsugu H, Yokoi T, Tateno C, Kataoka M, Horie T, Yoshizato K, Naito S. 2005. Evaluation of mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mouse with humanized liver. Xenobiotica. 35(9):877–890.
  • Ohshita H, Tateno C. 2017. Propagation of human hepatocytes in uPA/SCID mice: producing chimeric mice with humanized liver. Methods Mol Biol. 1506:91–100.
  • Ohtsuki S, Kawakami H, Inoue T, Nakamura K, Tateno C, Katsukura Y, Obuchi W, Uchida Y, Kamiie J, Horie T et al. 2014. Validation of uPA/SCID mouse with humanized liver as a human liver model: protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases by LC-MS/MS. Drug Metab Dispos. 42(6):1039–1043.
  • Tateno C, Kawase Y, Tobita Y, Hamamura S, Ohshita H, Yokomichi H, Sanada H, Kakuni M, Shiota A, Kojima Y et al. 2015. Generation of novel chimeric mice with humanized livers by using hemizygous cDNA-uPA/SCID mice. PLOS One. 10(11):e0142145.

References

  • Bergman A, Carvajal-Gonzalez S, Tarabar S, Saxena AR, Esler WP, Amin NB. 2020. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a liver-targeting acetyl-CoA carboxylase inhibitor (PF-05221304): a three-part randomized phase 1 study. Clin Pharmacol Drug Dev. 9(4):514–526.
  • 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.
  • Di L, Rong H, Feng B. 2013. Demystifying brain penetration in central nervous system drug discovery. Miniperspective. J Med Chem. 56(1):2–12.
  • Karunakaran S, Ramachandran S, Coothankandaswamy V, Elangovan S, Babu E, Periyasamy-Thandavan S, Gurav A, Gnanaprakasam JP, Singh N, Schoenlein PV, et al. 2011. SLC6A14 (ATB0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. J Biol Chem. 286(36):31830–31838.
  • Lai Y, Hsiao P. 2014. Beyond the ITC White Paper: emerging sciences in drug transporters and opportunities for drug development. Curr Pharm Des. 20(10):1577–1594.
  • Oswald S, Gröer C, Drozdzik M, Siegmund W. 2013. Mass spectrometry-based targeted proteomics as a tool to elucidate the expression and function of intestinal drug transporters. AAPS J. 15(4):1128–1140.
  • Tu M, Mathiowetz AM, Pfefferkorn JA, Cameron KO, Dow RL, Litchfield J, Di L, Feng B, Liras S. 2013. Medicinal chemistry design principles for liver targeting through OATP transporters. Curr Top Med Chem. 13(7):857–866.
  • Varma MV, El-Kattan AF, Feng B, Steyn SJ, Maurer TS, Scott DO, Rodrigues AD, Tremaine LM. 2017. Extended Clearance Classification System (ECCS) informed approach for evaluating investigational drugs as substrates of drug transporters. Clin Pharmacol Ther. 102(1):33–36.
  • Zamek-Gliszczynski MJ, Lee CA, Poirier A, Bentz J, Chu X, Ellens H, Ishikawa T, Jamei M, Kalvass JC, Nagar S, et al. 2013. ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin Pharmacol Ther. 94(1):64–79.

References

  • Jones NS, Yoshida K, Salphati L, Kenny JR, Durk MR, Chinn LW. 2020. Complex DDI by fenebrutinib and the use of transporter endogenous biomarkers to elucidate the mechanism of DDI. Clin Pharmacol Ther. 107(1):269–277.
  • Pan Y, Hsu V, Grimstein M, Zhang L, Arya V, Sinha V, Grillo JA, Zhao P. 2016. The application of physiologically based pharmacokinetic modeling to predict the role of drug transporters: scientific and regulatory perspectives. J Clin Pharmacol. 56(Suppl 7):S122–S131.
  • Taskar KS, Pilla Reddy V, Burt H, Posada MM, Varma M, Zheng M, Ullah M, Emami Riedmaier A, Umehara KI, Snoeys J et al. 2020. Physiologically-based pharmacokinetic models for evaluating membrane transporter mediated drug-drug interactions: current capabilities, case studies, future opportunities, and recommendations. Clin Pharmacol Ther. 107(5):1082–1115.
  • Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Kimoto E, Rodrigues AD, Chiba K, Sugiyama Y. 2018. PBPK modeling of coproporphyrin I as an endogenous biomarker for drug interactions involving inhibition of hepatic OATP1B1 and OATP1B3. CPT Pharmacometrics Syst Pharmacol. 7(11):739–747.

References

  • Matthaei J, Kuron D, Faltraco F, Knoch T, Dos Santos Pereira JN, Abu Abed M, Prukop T, Brockmoller J, Tzvetkov MV. 2016. OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics. Clin Pharmacol Ther. 99(6):633–641.
  • 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.

References

  • Akamine Y, Miura M, Komori H, Saito S, Kusuhara H, Tamai I, Ieiri I, Uno T, Yasui-Furukori N. 2014. Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers. Eur J Clin Pharmacol. 70(9):1087–1095.
  • Kashihara Y, Ieiri I, Yoshikado T, Maeda K, Fukae M, Kimura M, Hirota T, Matsuki S, Irie S, Izumi N et al. 2017. Small-dosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1 and ABCG2), and interaction (atorvastatin and grapefruit juice) profiles of 5 probes for OATP2B1 and BCRP. J Pharm Sci. 106(9):2688–2694.
  • Medwid S, Li MMJ, Knauer MJ, Lin K, Mansell SE, Schmerk CL, Zhu C, Griffin KE, Yousif MD, Dresser GK et al. 2019. Fexofenadine and rosuvastatin pharmacokinetics in mice with targeted disruption of organic anion transporting polypeptide 2B1. Drug Metab Dispos. 47(8):832–842.
  • Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ. 2009. Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics. 19(2):129–138.
  • Tapaninen T, Neuvonen PJ, Niemi M. 2011. Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol. 71(5):718–726.
  • Johnson M, Patel D, Matheny C, Ho M, Chen L, Ellens H. 2017. Inhibition of intestinal OATP2B1 by the calcium receptor antagonist ronacaleret results in a significant drug-drug interaction by causing a 2-fold decrease in exposure of rosuvastatin. Drug Metab Dispos. 45(1):27–34.
  • 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.

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:

Order Reprints Request Corporate Permissions

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:

Request Academic Permissions

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.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.