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Abstract
Elucidation of the key mechanisms that confer interindividual differences in drug response remains an important focus of drug disposition and clinical pharmacology research. We now know both environmental and host genetic factors contribute to the apparent variability in drug efficacy or in some cases, toxicity. In addition to the widely studied and recognized genes involved in the metabolism of drugs in clinical use today, we now recognize that membrane-bound proteins, broadly referred to as transporters, may be equally as important to the disposition of a substrate drug, and that genetic variation in drug transporter genes may be a major contributor of the apparent intersubject variation in drug response, both in terms of attained plasma and tissue drug level at target sites of action. Of particular relevance to drug disposition are members of the ATP Binding Cassette (ABC) superfamily of efflux transporters. In this review a comprehensive assessment and annotation of recent findings in relation to genetic variation in the Multidrug Resistance Proteins 1–5 (ABCC1-5) and Breast Cancer Resistance Protein (ABCG2) are described, with particular emphasis on the impact of such transporter genetic variation to drug disposition or efficacy.
| ABBREVIATIONS AND SYMBOLS | ||
| DJS: | = | Dubin-Johnson Syndrome |
| AML: | = | Acute Myeloid Leukemia |
| ABC: | = | ATP-Binding Cassette |
| ABCP: | = | Placenta specific ABC-transporter |
| ALL: | = | Acute Lymphoblastic Leukemia |
| ATP: | = | Adenosine Triphospate |
| BCRP: | = | Breast Cancer Resistance Protein |
| E17βG: | = | Estradiol 17-β-D-glucuronide |
| Fs: | = | Frame shift |
| GSH: | = | Reduced glutathione |
| HMG-CoA: | = | 3hydroxy-3-methyl-glutaryl-Coenzyme A |
| LMV: | = | Lamivudine Triphosphate |
| LTC4: | = | Leucotriene C4 |
| MDR: | = | Multidrug Resistance |
| MRP: | = | Multidrug Resistance Protein |
| MTX: | = | Methotrexate |
| OAT: | = | Organic Anion Transporter |
| OATP: | = | Organic Anion Transporting Polypeptide |
| OCT: | = | Organic Cation Transporter |
| PBMC: | = | Peripheral Blood Mononuclear Cell |
| PMEA: | = | 9-(2-phosphonyl methoxy ethyl) adenine |
| SNP: | = | Single Nucleotide Polymorphism |
| *: | = | Truncated protein |
ACKNOWLEDGMENT
This work was supported in part by United States Public Health Service Grant GM31304 and the German Academic Exchange Service DAAD (U.G.).