PT - JOURNAL ARTICLE AU - A. David Rodrigues AU - Yurong Lai AU - Hong Shen AU - Manthena V.S. Varma AU - Andrew Rowland AU - Stefan Oswald TI - Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides; Where is the Evidence for its Relevance in Drug-Drug Interactions? AID - 10.1124/dmd.119.089615 DP - 2019 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.119.089615 4099 - http://dmd.aspetjournals.org/content/early/2019/12/23/dmd.119.089615.short 4100 - http://dmd.aspetjournals.org/content/early/2019/12/23/dmd.119.089615.full AB - 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 to cytochrome P450 3A4 (CYP3A4), P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance 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 versus 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 multi-dose RIF data is further complicated by its auto-induction, which likely leads to decreased inhibition of OATP. In the absence of more conclusive OATP induction data, caution is needed when modeling DDI involving multi-dose inducers such as RIF.SIGNIFICANCE STATEMENT Presently, there is limited direct clinical evidence supporting the notion that human liver and gut OATPs are inducible by agents like RIF. Such data need to be reconciled and will pose challenges when attempting to incorporate OATP induction into physiologically-based PK models. Although disparate sets of tissue biopsy (atorvastatin and CBZ) 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.