Transporter-Enzyme and Transporter-Transporter Interplay in Predicting Drug Absorption and Disposition

Date: June 21 2018
Presenter(s): Leslie Z. Benet

Summary of the Presentation:

In 2005, Wu and Benet (Pharm Res 22:11-23) noted that a Biopharmaceutics Drug Disposition Classification System (BDDCS) could serve as the basis for predicting the importance of transporters in determining drug bioavailability and disposition.  They reasoned that for highly soluble, highly permeable Class 1 compounds, metabolism would be the major route of elimination and that transporter effects on availability and disposition would be negligible. In contrast for the poorly permeable, high solubility Class 3 compounds and the poorly permeable, poorly soluble Class 4 compounds, metabolism would only play a minor role in drug elimination, with renal and biliary excretion of unchanged drug being the predominant routes of elimination.  Uptake transporters would be major determinants of the bioavailability of these poorly permeable drugs and both uptake and efflux transporters could be important for drug elimination.

Highly permeable, poorly soluble, extensively metabolized Class 2 compounds constitute the majority of new molecular entities (NMEs) (~60%) and present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter-enzyme interplay. Uptake transporters are unimportant for gut bioavailability, but can play a major role in hepatic elimination.  Efflux transporters have major effects on bioavailability, metabolism and elimination of Class 2 drugs.  In this talk I will review our cellular, animal and human studies to define transporter-enzyme and transporter-transporter interplav.

About the presenter:

BENET, Leslie Z., PhD

Professor Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University of California San Francisco, CA, USA


Dr. Benet, Professor and former Chairman (1978-1998), Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, received his A.B. (English), B.S. (Pharmacy), M.S. from the University of Michigan and Ph.D. from the University of California. He has received nine honorary doctorates. His research interests, more than 550 publications, 6 books and 12 patents are in the areas of pharmacokinetics, biopharmaceutics, drug delivery and pharmacodynamics. Dr. Benet is listed by Thompson Reuters as one of the most highly cited pharmacologists worldwide, with his published peer-reviewed papers cited more than 24,000 times. His recent work on the interplay of metabolic enzymes and transport proteins as related to oral bioavailability led to development of the Biopharmaceutics Drug Disposition Classification System (BDDCS). Dr. Benet was a Founder and first President of the American Association of Pharmaceutical Scientists (AAPS). Dr. Benet is an elected member of the National Academy of Medicine (formerly IOM) of the U.S. National Academy of Sciences and a member of the International Transporter Consortium.