Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 4

Pharmacokinetic and Pharmacodynamic Consequences of Drug Transporter Pharmacogenetics

Deanna L. Kroetz, Ph.D.
Department of Biopharmaceutical Sciences
University of California San Francisco

Drug transporters are highly expressed in eliminating organs, tissue barriers, and drug target cells and play an important role in regulating the cellular uptake and efflux of endo- and xenobiotics. As a result, drug transporters can influence both the pharmacokinetics and pharmacodynamics of numerous drugs and variation in the expression and function of these transporters can lead to interindividual variability in drug response. As part of the NIH-sponsored Pharmacogenetics Research Network, we have resequenced the coding, flanking intronic and basal promoter regions of a large number of ABC and SLC transporters in a large, ethnically diverse sample. Genetic diversity is dependent on the region of the gene and varies greatly across the transporters. Bioinformatic approaches and functional analysis of both common and rare polymorphisms have been used to identify those variants most likely to have an effect on clinical drug response. Finally, functionally significant variants are being evaluated in clinical studies of drug pharmacokinetics and response/toxicity. This presentation will focus on the ABC transporters and will illustrate how a complete understanding of the functional and clinical consequences of drug transporter polymorphisms can be used to improve therapy with new and existing compounds.

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