The AAPS Journal

, 21:69 | Cite as

Estimating In Vivo Fractional Contribution of OATP1B1 to Human Hepatic Active Uptake by Mechanistically Modeling Pharmacogenetic Data

Research Article


A reasonable estimate on the fractional contribution of transporters to total hepatic active uptake (FT) is a critical factor in understanding and predicting human clearance, drug-drug interaction, and pharmacokinetic variability for hepatic transporter substrates. FT values for organic-anion-transporting polypeptide (OATP) 1B1 have been previously determined using in vitro assays. However, to date, none of the published in vitro FT values has been validated against or compared with in vivo FT values due to the lack of clinical data from selective substrates or inhibitors. The possible transporter-dependent in vitro to in vivo scaling further weakens the predictive power of these in vitro–determined FT values. In facing this challenge, a method is developed in this study to estimate in vivo OATP1B1 FT values by mechanistically modeling genotyped clinical pharmacokinetic data. The method is based on the hypothesis that observed change in hepatic active uptake clearance due to OATP1B1 polymorphism depends on two factors: (1) the contribution of OATP1B1 to the hepatic active uptake clearance and (2) the change of OATP1B1-mediated intrinsic uptake activity by the polymorphism. Conversely, if the changes caused by genetic variations in hepatic active uptake clearance and in OATP1B1-mediated clearance are known, then the OATP1B1 contribution to the hepatic active uptake clearance can be calculated. This is the first time that in vivo hepatic transporter FT values and a method to estimate these values are reported. Both FT values and the estimation method will facilitate future understanding and prediction on the transporter-mediated drug disposition.


OATP1B1 fractional contribution hepatic transporter modeling and simulation pharmacogenetics 


Supplementary material (12 kb)
ESM 1 (ZIP 11 kb)
12248_2019_337_MOESM2_ESM.docx (133 kb)
ESM 2 (DOCX 132 kb)


  1. 1.
    Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693–705.CrossRefGoogle Scholar
  2. 2.
    Li R, Barton HA, Varma MV. Prediction of pharmacokinetics and drug-drug interactions when hepatic transporters are involved. Clin Pharmacokinet. 2014;53(8):659–78.CrossRefGoogle Scholar
  3. 3.
    Li R, Barton HA, Yates PD, Ghosh A, Wolford AC, Riccardi KA, et al. A “middle-out” approach to human pharmacokinetic predictions for OATP substrates using physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn. 2014;41(3):197–209.CrossRefGoogle Scholar
  4. 4.
    Li R, Barton HA, Maurer TS. Toward prospective prediction of pharmacokinetics in OATP1B1 genetic variant populations. CPT Pharmacometrics Syst Pharmacol. 2014;3:e151.CrossRefGoogle Scholar
  5. 5.
    Jamei M, Bajot F, Neuhoff S, Barter Z, Yang J, Rostami-Hodjegan A, et al. A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine. Clin Pharmacokinet. 2014;53(1):73–87.CrossRefGoogle Scholar
  6. 6.
    Yang X, Atkinson K, Di L. Novel cytochrome P450 reaction phenotyping for low-clearance compounds using the hepatocyte relay method. Drug Metab Dispos. 2016;44(3):460–5.CrossRefGoogle Scholar
  7. 7.
    Williamson B, Soars AC, Owen A, White P, Riley RJ, Soars MG. Dissecting the relative contribution of OATP1B1-mediated uptake of xenobiotics into human hepatocytes using siRNA. Xenobiotica. 2013;43(10):920–31.CrossRefGoogle Scholar
  8. 8.
    Hirano M, Maeda K, Shitara Y, Sugiyama Y. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004;311(1):139–46.CrossRefGoogle Scholar
  9. 9.
    Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y. Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006;34(7):1247–54.CrossRefGoogle Scholar
  10. 10.
    Yamada A, Maeda K, Kamiyama E, Sugiyama D, Kondo T, Shiroyanagi Y, et al. Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos. 2007;35(12):2166–76.CrossRefGoogle Scholar
  11. 11.
    Kunze A, Huwyler J, Camenisch G, Poller B. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos. 2014;42(9):1514–21.CrossRefGoogle Scholar
  12. 12.
    Bi YA, Scialis RJ, Lazzaro S, Mathialagan S, Kimoto E, Keefer J, et al. Reliable rate measurements for active and passive hepatic uptake using plated human hepatocytes. AAPS J. 2017;19(3):787–96.CrossRefGoogle Scholar
  13. 13.
    Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006;130(6):1793–806.CrossRefGoogle Scholar
  14. 14.
    Bi YA, Qiu X, Rotter CJ, Kimoto E, Piotrowski M, Varma MV, et al. Quantitative assessment of the contribution of sodium-dependent taurocholate co-transporting polypeptide (NTCP) to the hepatic uptake of rosuvastatin, pitavastatin and fluvastatin. Biopharm Drug Dispos. 2013;34(8):452–61.CrossRefGoogle Scholar
  15. 15.
    Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81.CrossRefGoogle Scholar
  16. 16.
    Choi MK, Shin HJ, Choi YL, Deng JW, Shin JG, Song IS. Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. Xenobiotica. 2011;41(1):24–34.CrossRefGoogle Scholar
  17. 17.
    Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K. Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics. 2005;15(7):513–22.CrossRefGoogle Scholar
  18. 18.
    Li R, Barton HA. Explaining ethnic variability of transporter substrate pharmacokinetics in healthy Asian and Caucasian subjects with allele frequencies of OATP1B1 and BCRP: a mechanistic modeling analysis. Clin Pharmacokinet. 2018;57(4):491–503.CrossRefGoogle Scholar
  19. 19.
    Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.CrossRefGoogle Scholar
  20. 20.
    Wu HF, Hristeva N, Chang J, Liang X, Li R, Frassetto L, et al. Rosuvastatin pharmacokinetics in Asian and White subjects wild type for both OATP1B1 and BCRP under control and inhibited conditions. J Pharm Sci. 2017;106(9):2751–7.CrossRefGoogle Scholar
  21. 21.
    Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, et al. Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability. Eur J Pharm Sci. 2010;40(2):125–31.CrossRefGoogle Scholar
  22. 22.
    Singhvi SM, Pan HY, Morrison RA, Willard DA. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol. 1990;29(2):239–43.CrossRefGoogle Scholar
  23. 23.
    Martin PD, Warwick MJ, Dane AL, Brindley C, Short T. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther. 2003;25(10):2553–63.CrossRefGoogle Scholar
  24. 24.
    Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82(6):726–33.CrossRefGoogle Scholar
  25. 25.
    Lee YJ, Lee MG, Lim LA, Jang SB, Chung JY. Effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Korean subjects. Int J Clin Pharmacol Ther. 2010;48(1):36–45.CrossRefGoogle Scholar
  26. 26.
    Niemi M, Kivisto KT, Hofmann U, Schwab M, Eichelbaum M, Fromm MF. Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br J Clin Pharmacol. 2005;59(5):602–4.CrossRefGoogle Scholar
  27. 27.
    Zhang W, He YJ, Han CT, Liu ZQ, Li Q, Fan L, et al. Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide. Br J Clin Pharmacol. 2006;62(5):567–72.CrossRefGoogle Scholar
  28. 28.
    Oh ES, Kim CO, Cho SK, Park MS, Chung JY. Impact of ABCC2, ABCG2 and SLCO1B1 polymorphisms on the pharmacokinetics of pitavastatin in humans. Drug Metab Pharmacokinet. 2013;28(3):196–202.CrossRefGoogle Scholar
  29. 29.
    Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C, et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics. 2004;14(7):429–40.CrossRefGoogle Scholar
  30. 30.
    Niemi M, Pasanen MK, Neuvonen PJ. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther. 2006;80(4):356–66.CrossRefGoogle Scholar
  31. 31.
    Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG, et al. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics. 2007;17(8):647–56.CrossRefGoogle Scholar
  32. 32.
    Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73(6):554–65.CrossRefGoogle Scholar
  33. 33.
    Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK, et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther. 2005;77(6):468–78.CrossRefGoogle Scholar
  34. 34.
    Kalliokoski A, Backman JT, Kurkinen KJ, Neuvonen PJ, Niemi M. Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism. Clin Pharmacol Ther. 2008;84(4):488–96.CrossRefGoogle Scholar
  35. 35.
    Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M. The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol. 2008;66(6):818–25.CrossRefGoogle Scholar
  36. 36.
    Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. J Clin Pharmacol. 2008;48(3):311–21.CrossRefGoogle Scholar
  37. 37.
    Zhu J, Song M, Tan HY, Huang LH, Huang ZJ, Liu C, et al. Effect of pitavastatin in different SLCO1B1 backgrounds on repaglinide pharmacokinetics and pharmacodynamics in healthy Chinese males. Pak J Pharm Sci. 2013;26(3):577–84.PubMedGoogle Scholar
  38. 38.
    Sui SM, Wen JH, Li XH, Xiong YQ. Effect of OATP1B1 521T --> C heterogenesis on pharmacokinetic characterstics of rosuvastatin in Chinese volunteers. Yao Xue Xue Bao. 2011;46(6):695–700.PubMedGoogle Scholar
  39. 39.
    Choi JH, Lee MG, Cho JY, Lee JE, Kim KH, Park K. Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther. 2008;83(2):251–7.CrossRefGoogle Scholar
  40. 40.
    Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, et al. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol. 2014;78(3):587–98.CrossRefGoogle Scholar
  41. 41.
    Nies AT, Niemi M, Burk O, Winter S, Zanger UM, Stieger B, et al. Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1. Genome Med. 2013;5(1):1.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Systems Modeling and Simulation, Medicine DesignPfizer Worldwide R&DCambridgeUSA

Personalised recommendations