Drug Transporters: Safety Implications and Predictive Toxicology

Organizer: David Brewster, Hoffman-La Roche

Speakers: Ellen Priest, Hoffman-La Roche; Keith Hoffmaster, Pfizer; Reina Bendayan, University of Toronto; Raymond Evers, Merck & Co

The aim of the Predictive Toxicology Discussion Group is to bring experts from basic research together with toxicologists traditionally based in development to accelerate the adoption of new techniques that may increase the predictive power of toxicology studies. Leading scientists working at the forefront of their discipline will discuss their research and how application of the latest advancements in science can improve the pace of technological advancement in toxicology. By providing a neutral forum for the active collaboration of toxicologists with their cross-disciplinary colleagues, this group expects the future of toxicology to have increased generation of faster, low-cost, high-throughput assays; better prediction of toxic responses; and an improved understanding of the underlying molecular mechanisms contributing to a toxic response.

Presentations

Introduction to Drug Transporters
Ellen Priest, PhD
Hoffman-La Roche

Recently, it has been recognized that drug transporters play a significant role in the absorption, distribution, metabolism and excretion of drugs. However, the mechanisms and roles of many transporters are still poorly understood. Much attention has been placed on the drug efflux transporter P-glycoprotein (P-gp, MDR1) and its role in ADME, leading to the recent draft guidance from the FDA. In addition to P-gp, there are several members of the ATP Binding Cassette (ABC) family of transporters such as the multidrug resistance associated protein (MRP2), the breast cancer resistance protein (BCRP) and the bile salt export pump (BSEP) that mediate ATP-dependent transport of drugs out of cells. There are also a number of drug uptake transporters that are members of the solute carrier family which include organic anion transporting polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), dipeptide transporters (PEPT1 and PEPT2) and the sodium taruocholate cotransporting polypeptide (NTCP). Both the efflux and uptake transporters are expressed in polarized cells of organs, such as the liver and kidney, which are involved in drug metabolism and elimination. In this talk, the various drug transporters, their function, localization, role in ADME and potential for mediating drug-drug interactions will be presented.

Elucidating the Role of Drug Transporters in Hepatic Toxicity
Keith A. Hoffmaster, PhD
Pfizer Research Technology Center

Over the past decade, the explosion of molecular biology has enabled a number of hepatic transporters to be cloned and expressed into various in vitro experimental systems. Because of these advances, significant progress has been made in understanding the role that these mechanisms may play with respect to drug disposition. However, we are only now realizing that these mechanisms could also impact the toxicity of a drug that enters the liver. This talk will cover a brief introduction to transporters in the liver, highlight current methodologies employed to study hepatic transporters in the pharmaceutical industry, as well as describe some novel approaches to integrating transporters with other liver-based mechanisms (e.g. metabolism) for predicting overall liver disposition/toxicity. Finally, a case study using an example of a probe substrate will highlight the potential involvement of transporters in producing a toxic response, as well as underscore the significant complexity of hepatic drug disposition.

Clinical Implications of Drug Transport in the Brain
Reina Bendayan, Pharm D
University of Toronto

Several families of membrane transport proteins can significantly regulate drug distribution in the central nervous system. In particular, members of the ATP-binding Cassette (ABC) superfamily of transporters, such as P-