CYP2B6 ACTIVITY AND DRUG EFFECTS

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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. CYP3A metabolizes methadone in vitro, and for many years it was assumed that CYP3A was responsible for human methadone metabolism and disposition in vivo. However, it is now clear that human methadone disposition is not governed by CYP3A activity. The predominant CYP responsible for human methadone clearance and disposition in vivo remains to be identified. CYP2B6 is a major determinant of methadone metabolism in vivo, and indirect evidence suggests a role for CYP2B6 in vivo. This investigation will test the hypothesis that CYP2B6 is a predominant enzyme responsible for human methadone N-demethylation, kinetics and clinical effects in humans in vivo. A crossover investigation in healthy volunteers will evaluate the metabolism and disposition of methadone in the absence and presence of ticlopidine, a selective inhibitor of human CYP2B6 activity.