A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions

Abstract

Purpose

To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs.

Methods

A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600 mg, p.o.) and itraconazole (CYP3A inhibitor; 200 mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively. Based on the extended clearance concept, in vivo β values (fraction of metabolism plus biliary excretion among all the intracellular fates of drugs including basolateral efflux) and Rdif values (ratio of diffusional uptake to active uptake) were estimated.

Results

Rifampicin increased plasma AUCs of bosentan (×3.2), repaglinide (×1.9), clarithromycin (×1.9) and simeprevir (×7.2). Itraconazole increased those of clarithromycin (×2.3), simeprevir (×2.2) and midazolam (×3.7), which had relatively small β values. The plasma AUC of bosentan (with relatively large β and small Rdif) was dominated by OATP-mediated uptake. The AUC of simeprevir was also dominated by OATP-mediated uptake because of its small Rdif value.

Conclusions

The DDI study clarified the rate-determining processes of OATP/CYP3A substrates. Our analyses provide valuable information for predicting complex drug–drug interactions involving multiple processes.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

AUC:

Area under the plasma concentration–time curve

AUCR:

AUC ratio

CL:

Clearance

CLh :

Hepatic clearance

CLint,all :

Overall hepatic intrinsic clearance

CLint,bile :

Intrinsic clearance of biliary excretion

CLint,met :

Intrinsic clearance of hepatic metabolism

CLR :

Renal clearance

CYP:

Cytochrome P450

DDI:

Drug-drug interaction

DIDB:

University of Washington’s metabolism and transporter drug interaction database program

ECCS:

Extended clearance classification system

ECCCS:

Extended clearance concept classification system

Fa :

Fraction of the oral dose that enters the gut wall

fB :

Protein unbound fraction in blood

Fg :

Fraction of drug passing on to the portal circulation

Fh :

Hepatic availability

fm,CYP3A :

Contribution of CYP3A to the overall metabolic activity

fOATP1Bs :

Fraction of OATP1Bs-mediated transport in the hepatic intrinsic uptake clearance

IRh,CYP3A :

Inhibition ratio for CYP3A by itraconazole

IRh,OATP1Bs :

Inhibition ratio for OATP1Bs by rifampicin

IVIVE:

in vitro-in vivo extrapolation

NTCP:

Na+-taurocholate cotransporting polypeptide

OATP:

Organic anion transporting polypeptide

PBPK:

Physiologically-based pharmacokinetic

PS:

Permeability surface area-product

PSact,eff :

Intrinsic active efflux clearance on sinusoidal membrane

PSact,inf :

Intrinsic active uptake clearance on sinusoidal membrane

PSdif,eff :

Intrinsic efflux clearance by passive diffusion on sinusoidal membrane

PSdif,inf :

Intrinsic influx clearance by passive diffusion on sinusoidal membrane

Qh :

Hepatic blood flow rate

RB :

Blood-to-plasma concentration ratio

Rdif :

Ratio of PSdif,inf to PSact,inf

SCHH:

Sandwich-cultured human hepatocyte

UDP-glucuronosyltransferase:

UGT

References

  1. 1.

    Yoshikado T, Yoshida K, Kotani N, Nakada T, Asaumi R, Toshimoto K, Maeda K, Kusuhara H, Sugiyama Y. Quantitative analyses of hepatic OATP-mediated interactions between statins and inhibitors using PBPK modeling with a parameter optimization method. Clin Pharmacol Ther. 2016;100(5):513–23.

    CAS  Article  Google Scholar 

  2. 2.

    Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Meta Dispoition: Biol Fate Chem. 2015;43(11):1823–37.

    CAS  Article  Google Scholar 

  3. 3.

    Zamek-Gliszczynski MJ, Lee CA, Poirier A, Bentz J, Chu X, Ellens H, Ishikawa T, Jamei M, Kalvass JC, Nagar S, Pang KS, Korzekwa K, Swaan PW, Taub ME, Zhao P, Galetin A, International Transporter C. ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin Pharmacol Ther. 2013;94(1):64–79.

    CAS  Article  Google Scholar 

  4. 4.

    Watanabe T, Kusuhara H, Sugiyama Y. Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transporter-mediated distribution and clearance in humans. J Pharmacokinet Pharmacodyn. 2010;37(6):575–90.

    CAS  Article  Google Scholar 

  5. 5.

    Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y, Yamane N, Kumagai Y, Sugiyama Y. Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther. 2011;90(4):575–81.

    CAS  Article  Google Scholar 

  6. 6.

    Treiber A, Schneiter R, Hausler S, Stieger B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin a, rifampicin, and sildenafil. Drug Meta Dispoition: Biol Fate Chem. 2007;35(8):1400–7.

    CAS  Article  Google Scholar 

  7. 7.

    Varma MV, Bi YA, Kimoto E, Lin J. Quantitative prediction of transporter- and enzyme-mediated clinical drug-drug interactions of organic anion-transporting polypeptide 1B1 substrates using a mechanistic net-effect model. J Pharmacol Exp Ther. 2014;351(1):214–23.

    Article  Google Scholar 

  8. 8.

    Hartkoorn RC, Kwan WS, Shallcross V, Chaikan A, Liptrott N, Egan D, Sora ES, James CE, Gibbons S, Bray PG, Back DJ, Khoo SH, Owen A. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics. 2010;20(2):112–20.

    CAS  Article  Google Scholar 

  9. 9.

    Snoeys J, Beumont M, Monshouwer M, Ouwerkerk-Mahadevan S. Mechanistic understanding of the nonlinear pharmacokinetics and intersubject variability of simeprevir: a PBPK-guided drug development approach. Clin Pharmacol Ther. 2016;99(2):224–34.

    CAS  Article  Google Scholar 

  10. 10.

    Higgins JW, Ke AB, Zamek-Gliszczynski MJ. Clinical CYP3A inhibitor alternatives to ketoconazole, clarithromycin and itraconazole, are not transported into the liver by hepatic organic anion transporting polypeptides and organic cation transporter 1. Drug Meta Dispoition: Biol Fate Chem. 2014;42(11):1780–4.

    Article  Google Scholar 

  11. 11.

    Weber C, Schmitt R, Birnboeck H, Hopfgartner G, Eggers H, Meyer J, van Marle S, Viischer HW, Jonkman JH. Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J Clin Pharmacol. 1999;39(7):703–14.

    CAS  Article  Google Scholar 

  12. 12.

    Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol. 2005;97(4):249–56.

    CAS  Article  Google Scholar 

  13. 13.

    De Bruyn T, Stieger B, Augustijns PF, Annaert PP. Clearance prediction of HIV protease inhibitors in man: role of hepatic uptake. J Pharm Sci. 2016;105(2):854–63.

    CAS  Article  Google Scholar 

  14. 14.

    Rodrigues AD, Roberts EM, Mulford DJ, Yao Y, Ouellet D. Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily. Drug Meta Dispoition: Biol Fate Chem. 1997;25(5):623–30.

    CAS  Google Scholar 

  15. 15.

    Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089–115.

    CAS  Article  Google Scholar 

  16. 16.

    Honkalammi J, Niemi M, Neuvonen PJ, Backman JT. Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses. Drug Meta Dispoition: Biol Fate Chem. 2011;39(10):1977–86.

    CAS  Article  Google Scholar 

  17. 17.

    Kudo T, Hisaka A, Sugiyama Y, Ito K. Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes. Drug Meta Dispoition: Biol Fate Chem. 2013;41(2):362–71.

    CAS  Article  Google Scholar 

  18. 18.

    Sall C, Houston JB, Galetin A. A comprehensive assessment of repaglinide metabolic pathways: impact of choice of in vitro system and relative enzyme contribution to in vitro clearance. Drug Meta Dispoition: Biol Fate Chem. 2012;40(7):1279–89.

    CAS  Article  Google Scholar 

  19. 19.

    Roberts MS, Rowland M. A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations. J Pharmacokinet Biopharm. 1986;14(3):227–60.

    CAS  Article  Google Scholar 

  20. 20.

    Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev. 1998;50(3):387–412.

    CAS  PubMed  Google Scholar 

  21. 21.

    Zhang X, Quinney SK, Gorski JC, Jones DR, Hall SD. Semiphysiologically based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite. Drug Meta Dispoition: Biol Fate Chem. 2009;37(8):1587–97.

    CAS  Article  Google Scholar 

  22. 22.

    Nordell P, Winiwarter S, Hilgendorf C. Resolving the distribution-metabolism interplay of eight OATP substrates in the standard clearance assay with suspended human cryopreserved hepatocytes. Mol Pharm. 2013;10(12):4443–51.

    CAS  Article  Google Scholar 

  23. 23.

    Vildhede A, Karlgren M, Svedberg EK, Wisniewski JR, Lai Y, Noren A, Artursson P. Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos. 2014;42(7):1210–8.

    Article  Google Scholar 

  24. 24.

    Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55(5):481–5.

    CAS  Article  Google Scholar 

  25. 25.

    Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81(2):194–204.

    CAS  Article  Google Scholar 

  26. 26.

    Honkalammi J, Niemi M, Neuvonen PJ, Backman JT. Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses. Clin Pharmacol Ther. 2012;91(5):846–55.

    CAS  Article  Google Scholar 

  27. 27.

    Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol. 2003;56(3):305–14.

    CAS  Article  Google Scholar 

  28. 28.

    Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001;299(2):620–8.

    CAS  PubMed  Google Scholar 

  29. 29.

    Lin X, Skolnik S, Chen X, Wang J. Attenuation of intestinal absorption by major efflux transporters: quantitative tools and strategies using a Caco-2 model. Drug Meta Dispoition: Biol Fate Chem. 2011;39(2):265–74.

    CAS  Article  Google Scholar 

  30. 30.

    Tachibana T, Kato M, Watanabe T, Mitsui T, Sugiyama Y. Method for predicting the risk of drug-drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein. Xenobiotica. 2009;39(6):430–43.

    CAS  Article  Google Scholar 

  31. 31.

    Te Brake LH, Russel FG, van den Heuvel JJ, de Knegt GJ, de Steenwinkel JE, Burger DM, Aarnoutse RE, Koenderink JB. Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters. Tuberculosis (Edinb). 2016;96:150–7.

    CAS  Article  Google Scholar 

  32. 32.

    Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, Stone JA, Ding Y, Witter R, Gibson C, Roupe K, Evers R, Wagner JA, Stoch A. Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design. Clin Pharmacol Ther. 2011;89(2):234–42.

    CAS  Article  Google Scholar 

  33. 33.

    Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos. 2013;34(1):45–78.

    CAS  Article  Google Scholar 

  34. 34.

    Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012;55(10):4740–63.

    CAS  Article  Google Scholar 

  35. 35.

    Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, Dempsey C, Rasmussen S, Houle R, Chan G, Cai X, Valesky R, Fraser IP, Stoch SA. 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.

    CAS  Article  Google Scholar 

  36. 36.

    Pfeifer ND, Yang K, Brouwer KL. Hepatic basolateral efflux contributes significantly to rosuvastatin disposition I: characterization of basolateral versus biliary clearance using a novel protocol in sandwich-cultured hepatocytes. J Pharmacol Exp Ther. 2013;347(3):727–36.

    CAS  Article  Google Scholar 

  37. 37.

    Jones HM, Barton HA, Lai Y, Bi YA, Kimoto E, Kempshall S, Tate SC, El-Kattan A, Houston JB, Galetin A, Fenner KS. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Meta Dispoition: Biol Fate Chem. 2012;40(5):1007–17.

    CAS  Article  Google Scholar 

  38. 38.

    Kotani N, Maeda K, Watanabe T, Hiramatsu M, Gong LK, Bi YA, Takezawa T, Kusuhara H, Sugiyama Y. Culture period-dependent changes in the uptake of transporter substrates in sandwich-cultured rat and human hepatocytes. Drug Meta Dispoition: Biol Fate Chem. 2011;39(9):1503–10.

    CAS  Article  Google Scholar 

  39. 39.

    Vildhede A, Mateus A, Khan EK, Lai Y, Karlgren M, Artursson P, Kjellsson MC. Mechanistic modeling of Pitavastatin disposition in sandwich-cultured human hepatocytes: a proteomics-informed bottom-up approach. Drug Meta Dispoition: Biol Fate Chem. 2016;44(4):505–16.

    CAS  Article  Google Scholar 

  40. 40.

    Shingaki T, Takashima T, Ijuin R, Zhang X, Onoue T, Katayama Y, Okauchi T, Hayashinaka E, Cui Y, Wada Y, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y. Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats. J Pharmacol Exp Ther. 2013;347(1):193–202.

    CAS  Article  Google Scholar 

  41. 41.

    Varma MV, Steyn SJ, Allerton C, El-Kattan AF. Predicting clearance mechanism in Drug discovery: extended clearance classification system (ECCS). Pharm Res. 2015;32(12):3785–802.

    CAS  Article  Google Scholar 

  42. 42.

    Kunze A, Poller B, Huwyler J, Camenisch G. Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins. Drug Metab Pers Ther. 2015;30(3):175–88.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements and Disclosures

This study was financially supported by Grant-in-Aid for Scientific Research (S) [Grant 24,229,002; TY, KM, YS].

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yuichi Sugiyama.

Ethics declarations

Wrote Manuscript: Takashi Yoshikado, Kazuya Maeda, Hiroyuki Kusuhara, and Yuichi Sugiyama.

Designed Research: Takashi Yoshikado, Kazuya Maeda, Sawako Furihata, Hiroyuki Kusuhara, Ken-ichi Furihata and Yuichi Sugiyama.

Performed Research: Takashi Yoshikado, Kazuya Maeda, Sawako Furihata, Hanano Terashima, Takeshi Nakayama, Keiko Ishigame, Kazunobu Tsunemoto, Hiroyuki Kusuhara, Ken-ichi Furihata and Yuichi Sugiyama.

Analyzed Data: Takashi Yoshikado, Kazuya Maeda, Hiroyuki Kusuhara, and Yuichi Sugiyama.

Electronic supplementary material

ESM 1

(PDF 1.13 MB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yoshikado, T., Maeda, K., Furihata, S. et al. A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions. Pharm Res 34, 1570–1583 (2017). https://doi.org/10.1007/s11095-017-2168-5

Download citation

Key words

  • Extended clearance concept
  • Hepatic uptake
  • Metabolism
  • Rate-determining process