ISSX Webinar: Induction of Drug Transporters in vitro and in vivo: From Gut ABCs to Liver SLCs and Back Again
Presented by David Rodrigues, Ph.D., Pfizer
Tuesday, September 15, 2020
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Various ATP-binding cassette (ABC) and solute carrier (SLC) transporters, expressed in the gut and liver, are known to govern the pharmacokinetics (PK), absorption, disposition, metabolism and excretion of drugs and endogenous compounds. Therefore, they present as the loci of important and well-documented drug-drug interactions (DDIs) involving inhibitory perpetrator drugs. Examples include intestinal breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp), as well as hepatic organic anion transporting polypeptides (OATP1B1, OATP1B3) and multidrug resistance-associated protein 2 (MRP2). However, compared to drug-metabolizing enzymes (e.g., cytochrome P450 3A4), and in some cases Pgp and MRP2, induction of SLCs by agents such as rifampicin (RIF) and carbamazepine (CBZ) is not well described. Clinically, there are two major challenges; (1) SLC drug probes are not well validated for multi-dose induction assessment. This is particularly evident when attempting to study the induction of liver OATPs using statins; most statins also present as substrates of induced P450, Pgp and MRP2; and (2) although the most direct way to assess transporter induction involves the expression profiling of gut and liver tissue following inducer administration, most investigators avoid developing study protocols necessitating pinch and needle biopsy procedures. Both serve to confound in vitro to in vivo extrapolations and the development of “extended” PBPK models incorporating transporter induction. At the same time, despite evidence that the expression of some transporters is induced in gut biopsies, most researchers are forced to conduct in vitro studies with currently available intestinal cell lines as surrogates for human primary enterocytes (e.g., Caco-2, LS180, T84, and LS174T).
During the webinar, evidence for and against transporter induction will be presented and ABC transporters will be compared to SLCs such as OATP1B1, OATP1B3 and OATP2B1. In vitro studies (cultured human primary hepatocytes and tissue slices) with known nuclear receptor (PXR, LXR, FXR, and CAR) agonists will be described. In vivo evidence for transporter induction will leverage available animal and human PK data (drug probes and biomarkers), as well as the expression profiling of human tissue following the administration of known inducers (e.g., RIF and CBZ). Finally, the concept of “liquid biopsy” (expression profiling of plasma-derived immunocaptured tissue-specific small extracellular vesicles) will be introduced.
About the Speaker:
||David Rodrigues has been in the pharmaceutical industry for 30 years and currently holds the title of Senior Scientific Director as head of the Transporter Sciences Group at Pfizer (Groton, CT). Before joining Pfizer in
2014, he spent productive periods at Searle, Abbott Labs, Merck, and Bristol-Myers Squibb. During that time, he served on both scientific (Associate Research Fellow, Senior Research Fellow) and managerial (Director, Senior
Director, Executive Director) ladders.
He has authored over a dozen book chapters, 163 peer-reviewed manuscripts, has presented at numerous (>70) scientific symposia/meetings, and served on the editorial boards of various
DMPK-related journals (e.g., Current Drug Metabolism, Drug Metabolism Letters, Xenobiotica, Drug Metabolism & Disposition). In addition, he has edited/co-edited three text books related to drug interactions and one on
the topic of drug metabolism. Presently, he is a member of the International Transporter Consortium (ITC) and also serves as adjunct professor at the College of Pharmacy, University of Rhode Island. In 2009, David was inducted
as Fellow of The American Association of Pharmaceutical Scientists (AAPS).