Pharmacogenomics
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Cytochrome P450 (CYP) 2C8 is responsible for the oxidative metabolism of many clinically available drugs from a diverse number of drug classes (e.g., thiazolidinediones, meglitinides, NSAIDs, antimalarials and chemotherapeutic taxanes). The CYP2C8 enzyme is encoded by the CYP2C8 gene, and several common nonsynonymous polymorphisms (e.g., CYP2C8*2 and CYP2C8*3) exist in this gene. The CYP2C8*2 and *3 alleles have been associated in vitro with decreased metabolism of paclitaxel and arachidonic acid. ⋯ Furthermore, clinical data regarding the impact of the CYP2C8*3 allele on the disposition of NSAIDs are conflicting and no definitive conclusions can be made at this time. The purpose of this review is to highlight these clinical studies that have investigated the association between CYP2C8 polymorphisms and CYP2C8 substrate pharmacokinetics and/or pharmacodynamics in humans. In this review, CYP2C8 clinical pharmacogenetic data are provided by drug class, followed by a discussion of the future of CYP2C8 clinical pharmacogenetic research.
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Although the frequencies of pharmacogenetic variants differ among racial groups, most pharmacogenetic algorithms for genotype-guided warfarin dosing only include two CYP2C9 alleles (*2 and *3) and a single VKORC1 allele (g.-1639G>A or g.1173C>T) commonly found among Caucasians. Therefore, this study sought to identify other CYP2C9 and VKORC1 alleles important in warfarin dose variability and to determine their frequencies in different racial and ethnic groups. ⋯ CYP2C9*8 is prevalent among African-Americans ( approximately 1 in 11 individuals). Thus, in this racial group, the incorporation of CYP2C9*8 into genotyping panels may improve dose prediction of CYP2C9-metabolized drugs, including warfarin.
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Multicenter Study Comparative Study
Thiopurine methyltransferase and thiopurine metabolite testing in patients with inflammatory bowel disease who are taking thiopurine drugs.
Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. ⋯ Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testing becomes available locally as a clinical service.
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Multicenter Study Comparative Study
Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management.
The use of medication in pain management currently involves empirical adjustment based on observed clinical outcome and the presence of adverse drug reactions. In this study, pharmacogenomics and therapeutic drug monitoring were used to evaluate the clinical effectiveness of genotyping chronic pain patients on analgesic therapy. It was hypothesized that patients who have inherited polymorphisms in CYP2D6 that make them poor or intermediate metabolizers of opioid medications would have higher steady-state concentrations of those opioids and may be more likely to experience adverse drug reactions. ⋯ These results suggest that patient care may be improved by genotyping and following therapeutic drug concentrations. Benefits include increased efficiency in proper drug selection, dose optimization and minimization of adverse drug reactions to improve patient outcome and safety. In addition, this study clearly demonstrated a relationship between oxycodone steady-state drug concentrations and pain relief. Future large-scale prospective studies are needed to confirm the clinical value of using genetic information to guide pain management therapy.
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Serious adverse drug reactions represent the sixth major cause of death in the USA, are the main reason for postmarketing drug withdrawal and represent billions of US dollars in costs every year in all developed countries. Some of these serious adverse drug reactions might be avoided by systematically screening for pharmacogenomic risk factors. ⋯ Recently published pharmacogenomic randomized, controlled and ongoing trials will progressively make genotyping tests, such as those for HLA-B*5701 (abacavir), TPMT (6-mercaptopurine), CYP2C9 plus VKORC1 (warfarin) and CYP3A5 (tacrolimus), mandatory. Parallel development of pharmacogenomic bed tests will certainly establish genetically-based prescriptions in routine medical practice.