Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes

Abstract.

Objective: Limited data suggest that CYP1A2 and CYP2D6 are involved in the metabolism of olanzapine. The purpose of this study was to further elucidate the role of these enzymes in the disposition of olanzapine in vivo. Methods: Seventeen healthy non-smoking male volunteers were included in the study. Five subjects were CYP2D6 poor metabolisers (PMs), and 12 were CYP2D6 extensive metabolisers (EMs). All subjects received a single oral dose of 7.5 mg olanzapine, and serum concentrations were measured for 96 h using gas chromatography. A cross-over study was undertaken in the 12 CYP2D6 EMs who at least 2 weeks before or after the olanzapine dose received a single oral dose of 200 mg caffeine. The concentrations of caffeine and paraxanthine were measured in saliva 10 h after caffeine intake, and the paraxanthine/caffeine ratio was calculated as a measure of CYP1A2 activity. Results: A threefold inter-individual variability in oral clearance (CL_oral) and maximum serum concentration (C_max) of olanzapine was observed and a 2.3-fold inter-individual variability in CYP1A2 activity. There was no significant correlation between CYP1A2 activity and oral clearance of olanzapine (r=–0.19, P=0.56). Moreover, there were no significant differences in any of the olanzapine pharmacokinetic parameters between the CYP2D6 PMs and EMs (CL_oral=0.246 l h^–1 kg^–1 and 0.203 l h^–1 kg^–1, respectively, P=0.30). Conclusion: Neither CYP1A2 nor CYP2D6 seem to have a dominating role in olanzapine biotransformation after intake of a single dose.