Clinical Investigation of Coproporphyrins as Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug–Drug Interactions

  • Annett Kunze
  • Emmanuel Njumbe Ediage
  • Lieve Dillen
  • Mario Monshouwer
  • Jan Snoeys
Original Research Article
  • 11 Downloads

Abstract

Introduction

Coproporphyrin (CP) I and III have recently been proposed as endogenous clinical biomarkers to predict organic anion-transporting polypeptide 1B (OATP1B)-mediated drug–drug interactions (DDIs). In the present study, we first investigated the in vitro selectivity of CPI and CPIII towards drug uptake and efflux transporters. We then assessed the in vivo biomarker sensitivity towards OATP1B inhibition.

Methods

To assess transporter selectivity, incubations with CPI and CPIII were performed in vitro, using single transporter-expressing and control systems. Furthermore, CPI and CPIII plasma concentrations were determined from participants of three independent clinical trials who were administered with either a strong, moderate, or mild clinical OATP1B inhibitor.

Results

Our results show that CPI and CPIII are substrates of OATP1B1, OATP1B3, the multidrug resistance-associated protein (MRP) 2, and MRP3. No substrate interaction was shown for other prominent drug transporters that have been associated with clinical DDIs. Results from clinical studies demonstrated that changes in CPI and CPIII plasma levels were predictive for moderate (two to threefold area under the concentration–time curve [AUC] increase) and strong (≥ fivefold increases) clinical OATP1B inhibition. Furthermore, CPI, but not CPIII, concentration changes were predictive for a mild clinically observed DDI where CPI AUC increases of 1.4-fold were comparable with those observed for pitavastatin as victim drug (AUC increases of 1.5-fold).

Conclusion

Our results demonstrate the selectivity of CPI and CPIII towards the OATP1B/MRP pathway, and the herein reported data further underline the potential of CPI and CPIII as selective and sensitive clinical biomarkers to quantify OATP1B-mediated DDIs.

Notes

Acknowledgements

The authors thank Sophie Jonkers for assistance in vesicle studies, Drs. Loeckie de Zwart and Marie-Emilie Willemin for assisting in the pharmacokinetic data analysis, and Dr. Frank Jacobs for reviewing the manuscript. We also thank all clinical project team representatives and Janssen colleagues who supported this study.

Compliance with Ethical Standards

Funding

This study was funded by Janssen Pharmaceuticals.

Conflicts of interest

Annett Kunze, Emmanuel Njumbe Ediage, Lieve Dillen, Mario Monshouwer and Jan Snoeys are full-time employees of Janssen Pharmaceuticals.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

40262_2018_648_MOESM1_ESM.doc (114 kb)
Supplementary material 1 (DOC 114 kb)

References

  1. 1.
    Maeda K. Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 as important regulators of the pharmacokinetics of substrate drugs. Biol Pharm Bull. 2015;38(2):155–68.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112(1):71–105.CrossRefPubMedGoogle Scholar
  4. 4.
    Vaidyanathan J, Yoshida K, Arya V, Zhang L. Comparing various in vitro prediction criteria to assess the potential of a new molecular entity to inhibit organic anion transporting polypeptide 1B1. J Clin Pharmacol. 2016;56(Suppl 7):S59–72.CrossRefPubMedGoogle Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    Feng B, Varma MV. Evaluation and quantitative prediction of renal transporter-mediated drug–drug interactions. J Clin Pharmacol. 2016;56(Suppl 7):S110–21.CrossRefPubMedGoogle Scholar
  7. 7.
    Varma MV, Lai Y, Feng B, Litchfield J, Goosen TC, Bergman A. Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug–drug interactions. Pharm Res. 2012;29(10):2860–73.CrossRefPubMedGoogle Scholar
  8. 8.
    Varma MV, Lai Y, Kimoto E, Goosen TC, El-Kattan AF, Kumar V. Mechanistic modeling to predict the transporter- and enzyme-mediated drug–drug interactions of repaglinide. Pharm Res. 2013;30(4):1188–99.CrossRefPubMedGoogle Scholar
  9. 9.
    Chu X, Chan GH, Evers R. Identification of endogenous biomarkers to predict the propensity of drug candidates to cause hepatic or renal transporter-mediated drug–drug interactions. J Pharm Sci. 2017;106(9):2357–67.CrossRefPubMedGoogle Scholar
  10. 10.
    Rodrigues AD, Taskar KS, Kusuhara H, Sugiyama Y. Endogenous probes for drug transporters: balancing vision with reality. Clin Pharmacol Ther. 2018;103(3):434–48.CrossRefPubMedGoogle Scholar
  11. 11.
    Bednarczyk D, Boiselle C. Organic anion transporting polypeptide (OATP)-mediated transport of coproporphyrins I and III. Xenobiotica. 2016;46(5):457–66.CrossRefPubMedGoogle Scholar
  12. 12.
    Lai Y, Mandlekar S, Shen H, Holenarsipur VK, Langish R, Rajanna P, et al. Coproporphyrins in plasma and urine can be appropriate clinical biomarkers to recapitulate drug–drug interactions mediated by organic anion transporting polypeptide inhibition. J Pharmacol Exp Ther. 2016;358(3):397–404.CrossRefPubMedGoogle Scholar
  13. 13.
    Shen H, Chen W, Drexler DM, Mandlekar S, Holenarsipur VK, Shields EE, et al. Comparative evaluation of plasma bile acids, dehydroepiandrosterone sulfate, hexadecanedioate, and tetradecanedioate with coproporphyrins I and III as markers of OATP inhibition in healthy subjects. Drug Metab Dispos. 2017;45(8):908–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Shen H, Dai J, Liu T, Cheng Y, Chen W, Freeden C, et al. Coproporphyrins I and III as functional markers of OATP1B activity. In vitro and in vivo evaluation in preclinical species. J Pharmacol Exp Ther. 2016;357(2):382–93.CrossRefPubMedGoogle Scholar
  15. 15.
    Kaplowitz N, Javitt N, Kappas A. Coproporphyrin I and 3 excretion in bile and urine. J Clin Investig. 1972;51(11):2895–9.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Shimizu Y, Naruto H, Ida S, Kohakura M. Urinary coproporphyrin isomers in Rotor’s syndrome: a study in eight families. Hepatology. 1981;1(2):173–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Gilibili RR, Chatterjee S, Bagul P, Mosure KW, Murali BV, Mariappan TT, et al. Coproporphyrin-I: a fluorescent, endogenous optimal probe substrate for ABCC2 (MRP2) suitable for vesicle-based MRP2 inhibition assay. Drug Metab Dispos. 2017;45(6):604–11.CrossRefPubMedGoogle Scholar
  18. 18.
    US FDA. In vitro metabolism- and transporter-mediated drug–drug interaction studies. Guidance for industry. 2017. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm581965.pdf. Accessed Nov 2017.
  19. 19.
    Cui Y, Konig J, Keppler D. Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol Pharmacol. 2001;60(5):934–43.CrossRefPubMedGoogle Scholar
  20. 20.
    Lau YY, Okochi H, Huang Y, Benet LZ. Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther. 2006;316(2):762–71.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shingaki T, Takashima T, Ijuin R, Zhang X, Onoue T, Katayama Y, et al. 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.CrossRefPubMedGoogle Scholar
  23. 23.
    Takashima T, Kitamura S, Wada Y, Tanaka M, Shigihara Y, Ishii H, et al. PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me. J Nucl Med. 2012;53(5):741–8.CrossRefPubMedGoogle Scholar
  24. 24.
    US FDA. Label information Livola. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022363s000lbl.pdf. Accessed Oct 2017.
  25. 25.
    Akamine Y, Miura M, Yasui-Furukori N, Kojima M, Uno T. Carbamazepine differentially affects the pharmacokinetics of fexofenadine enantiomers. Br J Clin Pharmacol. 2012;73(3):478–81.CrossRefPubMedGoogle Scholar
  26. 26.
    Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther. 1996;59(1):7–13.CrossRefPubMedGoogle Scholar
  27. 27.
    Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Investig. 1999;104(2):147–53.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001;69(3):114–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Kusuhara H, Miura M, Yasui-Furukori N, Yoshida K, Akamine Y, Yokochi M, et al. Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects. Drug Metab Dispos. 2013;41(1):206–13.CrossRefPubMedGoogle Scholar
  30. 30.
    Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet. 2003;42(9):819–50.CrossRefPubMedGoogle Scholar
  31. 31.
    Dixit V, Hariparsad N, Li F, Desai P, Thummel KE, Unadkat JD. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Dispos. 2007;35(10):1853–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, et al. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol. 2000;157(5):1575–80.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Martin P, Riley R, Back DJ, Owen A. Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells. Br J Pharmacol. 2008;153(4):805–19.CrossRefPubMedGoogle Scholar
  34. 34.
    Williamson B, Dooley KE, Zhang Y, Back DJ, Owen A. Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine. Antimicrob Agents Chemother. 2013;57(12):6366–9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Acocella G. Clinical pharmacokinetics of rifampicin. Clin Pharmacokinet. 1978;3(2):108–27.CrossRefPubMedGoogle Scholar
  36. 36.
    Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y, et al. 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.CrossRefPubMedGoogle Scholar
  37. 37.
    Barnett S, Ogungbenro K, Menochet K, Shen H, Lai Y, Humphreys WG, et al. Gaining mechanistic insight into coproporphyrin I as endogenous biomarker for OATP1B-mediated drug–drug interactions using population pharmacokinetic modeling and simulation. Clin Pharmacol Ther. 2017.  https://doi.org/10.1002/cpt.983 (Epub 15 Dec 2017).PubMedGoogle Scholar
  38. 38.
    Annaert P, Ye ZW, Stieger B, Augustijns P. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica. 2010;40(3):163–76.CrossRefPubMedGoogle Scholar
  39. 39.
    Ouwerkerk-Mahadevan S, Snoeys J, Peeters M, Beumont-Mauviel M, Simion A. Drug–drug interactions with the NS3/4A protease inhibitor simeprevir. Clin Pharmacokinet. 2016;55(2):197–208.CrossRefPubMedGoogle Scholar
  40. 40.
    Morrissey KM, Wen CC, Johns SJ, Zhang L, Huang SM, Giacomini KM. The UCSF-FDA TransPortal: a public drug transporter database. Clin Pharmacol Ther. 2012;92(5):545–6.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Huisman MT, Snoeys J, Monbaliu J, Martens M, Sekar V, Raoof A. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters [poster]. In: Presented at the 61st annual meeting of the American Association for the Study of Liver Disease (AASLD); 29 Oct–2 Nov 2010, San Francisco, CA.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Janssen Pharmaceutical Companies of Johnson & JohnsonBeerseBelgium

Personalised recommendations