1521-009X/48/3/205–216$35.00 https://doi.org/10.1124/dmd.119.089615 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 48:205–216, March 2020 Copyright ª 2020 by The American Society for Pharmacology and Experimental Therapeutics Minireview Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides: Where Is the Evidence for Its Relevance in Drug-Drug Interactions? s A. David Rodrigues, Yurong Lai, Hong Shen, Manthena V.S. Varma, Andrew Rowland, and Stefan Oswald ADME Sciences, Medicine Design, Worldwide Research & Development, Pfizer Inc., Groton, Connecticut (A.D.R., M.V.S.V.); Drug Metabolism Department, Gilead Sciences Inc., Foster City, California (Y.L.); Department of Metabolism & Pharmacokinetics, Bristol- Myers Squibb Research & Development, Princeton, New Jersey (H.S.); College of Medicine & Public Health, Flinders University, Adelaide, South Australia, Australia (A.R.); and Department of Clinical Pharmacology, Center of Drug Absorption & Transport, University Medicine of Greifswald, Greifswald, Germany (S.O.) Received October 14, 2019; accepted December 6, 2019 ABSTRACT Organic anion transporting polypeptides (OATPs), expressed in human liver (OATP1B1, OATP1B3, and OATP2B1) and intestine (OATP2B1), govern the pharmacokinetics (PK) of drugs (e.g., statins) and endogenous substrates (e.g., coproporphyrin I [CPI]). Their expression is known to be modulated (e.g., disease, age, and environmental factors), and they also present as the loci of clinically relevant polymorphisms and drug interactions involving inhibition. In comparison, relatively few clinical reports describe the induction of OATPs, although the effect of inducers (e.g., rifampicin [RIF], carbamazepine [CBZ]) on OATP biomarker plasma levels and statin PK has been reported. Of note, available human tissue (e.g., biopsy) protein and messenger RNA expression profiling data indicate that OATPs in gut and liver are not induced by prototypical inducers such as RIF when compared with cyto- chrome P450 3A4 (CYP3A4), P-glycoprotein (Pgp), multidrug resistance–associated protein 2 (MRP2), and breast cancer re- sistance protein (BCRP). Such results are consistent with in vitro human hepatocyte data. Therefore, the observed impact of RIF, and possibly CBZ, on statin PK (>20% decrease in the area under the plasma concentration vs. time curve) cannot be ascribed to OATP induction with certainty. In fact, most statins and CPI have been shown to present variously as substrates of RIF-inducible proteins such as CYP3A4, Pgp, MRP2, and BCRP. Interpretation of multidose RIF data is further complicated by its autoinduction, which likely leads to decreased inhibition of OATP. In the absence of more conclusive OATP induction data, caution is needed when modeling drug-drug interactions involving multidose inducers such as RIF. SIGNIFICANCE STATEMENT Presently, there is limited direct clinical evidence supporting the notion that human liver and gut organic anion transporting polypeptides (OATPs) are inducible by agents like rifampicin (RIF). Such data need to be reconciled and will pose challenges for attempting to incorporate OATP induction into physiologically based pharmacokinetics models. Although disparate sets of tissue biopsy (atorvastatin and carbamaze- pine) and in vitro hepatocyte (phenobarbital, chenodeoxycholate, and amprenavir) data present OATP messenger RNA induction (‡2-fold) by agents beyond RIF, the clinical relevance of such data needs to be determined. Introduction Of the various solute carriers (SLCs) known to be expressed in the human liver, two organic anion transporting polypeptides (OATPs), OATP1B1 and OATP1B3, are well characterized. A third OATP (OATP2B1) is ubiquitously expressed including the intestine and liver (Oscarson et al., 2006, 2007; Brueck et al., 2019). To a greater or lesser degree, each of the three is known to be involved in the pharmacoki- netics (PK) of various drugs (e.g., statins, sartans, gliptins), endogenous compounds (e.g., coproporphyrin isomers coproporphyrin I [CPI] and CPIII, bilirubin glucuronide, and amidated bile acid glucuronides and https://doi.org/10.1124/dmd.119.089615. s This article has supplemental material available at dmd.aspetjournals.org. ABBREVIATIONS: AADAC, arylacetamide deacetylase; ABC, ATP-binding cassette; AUC, area under the plasma concentration versus time curve; BCRP, breast cancer resistance protein; BSEP (ABCG2), bile salt export pump; CAR (NR1I3), constitutive androstane receptor; CBZ, carbamazepine; CPI, coproporphyrin I; CYP2C, cytochrome P450 2C; CYP3A4, cytochrome P450 3A4; DDI, drug-drug interaction; ECCS, extended clearance classification system; E max , maximal induction; FXR (NR1H4), farnesoid X receptor; LXRa (NR1H3), liver X receptor alpha; MRP2 (ABCC2), multidrug resistance–associated protein 2; OATP, organic anion transporting polypeptide; PBPK, physiologically based pharmacokinetics; Pgp (ABCB1), P-glycoprotein; PK, pharmacokinetics; PPAR, peroxisome proliferator–activated receptor; PXR (NR1I2), pregnane X-receptor; RIF, rifampicin; SLC, solute carrier. 205 http://dmd.aspetjournals.org/content/suppl/2019/12/23/dmd.119.089615.DC1 Supplemental material to this article can be found at: at ASPET Journals on February 18, 2022 dmd.aspetjournals.org Downloaded from