EFFECT OF CYTOCHROME P450 2B6 GENETIC POLYMORPHISM

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Efavirenz is an important drug in the therapy of HIV infection, but there is wide interindividual variability in its response: some patients fail therapy and approximately 50% of patients experience central nervous system (CNS) adverse effects after recommended therapeutic doses of efavirenz. Although most CNS side effects are mild and subside after repeated administration, about 10% of patients terminate therapy with efavirenz because of persistent and severe CNS adverse effects. The reason why some patients are at greater risk for failure of treatment or CNS adverse effects is not fully known. There is evidence in the literature that plasma concentrations of efavirenz predict CNS adverse effects and antiretroviral efficacy of efavirenz. Efavirenz pharmacokinetics has been reported to exhibit extensive intersubject variability. This is probably a reflection of variable expression of the CYP450s involved in its metabolism, as efavirenz undergoes extensive oxidation in the liver. Recently, we identified the genetically polymorphic enzyme CYP2B6 as the main isoform involved in efavirenz metabolism in vitro. These data suggest that the substantial difference in efavirenz pharmacokinetics and response may be due to variable CYP2B6 activity. Here, we propose a clinical trial to test the hypothesis that variable expression of CYP2B6 that result from functional polymorphisms in the CYP3B6 gene or exposure to drugs influence efavirenz pharmacokinetics and the resulting CNS adverse events. In addition, similar to other CYPs (e.g. CYP2C19), genetic variations of CYP2B6 may influence the susceptibility to metabolic inducers. To this end, we will determine the pharmacokinetics and CNS effects of a single 600 mg oral dose of efavirenz administered after pretreatment with rifampin (600 mg/day) or placebo pills for 10 days in healthy volunteers pregenotyped for functional CYP2B6 genetic variants.