Membrane Transporters in Drug Development

Abstract

Membrane transporters have wide, but specific tissue distributions. They can impact on multiple endogenous and xenobiotic processes. Knowledge and awareness within the pharmaceutical industry of their impact on drug absorption, distribution, metabolism and elimination (ADME) and drug safety is growing rapidly. Clinically important transporter-mediated drug-drug interactions (DDIs) have been observed. Up to nine diverse transporters are implicated in the DDIs of a number of widely prescribed drugs, posing a significant challenge to the pharmaceutical industry. There is a complex interplay between multiple transporters and/or enzymes in the ADME and pharmacogenomics of drugs. Integrating these different mechanisms to understand their relative contributions to ADME is a key challenge. Many different factors complicate the study of membrane transporters in drug development. These include a lack of specific substrates and inhibitors, non-standard invitro tools, and competing/complementary mechanisms (e.g. passive permeability and metabolism). Discovering and contextualizing the contribution of membrane transporters to drug toxicity is a significant new challenge. Drug interactions with key membrane transporters are routinely assessed for central nervous system (CNS) drug discovery therapies, but are not generally considered across the wider drug discovery. But, there is interest in utilizing membrane transporters as drug delivery agents. Computational modeling approaches, notably physiology-based/pharmacokinetic (PB/PK) modeling are increasingly applied to transporter interactions, and permit integration of multiple ADME mechanisms. Because of the range of tissues and transporters of interest, robust transporter, invitro to invivo, scaling factors are required. Empirical factors have been applied, but absolute protein quantitation will probably be required.