Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes

Objective: Limited data suggest that CYP1A2 and CYP2D6 are involved in the metabolism of olanzapine. The purpose of this study was to further elucidat e 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 CYP2 D6 extensive metabolisers (EMs). All subjects received a single oral dose o f 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 paraxanthi ne 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 (CLoral ) and maximum serum concentration (Cma,) of olanzapine was observed and a 2 .3-fold interindividual variability in CYP1A2 activity. There was no signif icant correlation between CYPIA2 activity and oral clearance of olanzapine (r=-0.19, P=0.56). Moreover, there were no significant differences in any o f the olanzapine pharmacokinetic parameters between the CYP2D6 PMs and EMs (CLoral = 0.2461 h(-1) kg(-1) and 0.203 1 h(-1) kg(-1), respectively, P = 0 .30). Conclusion: Neither CYP1A2 nor CYP2D6 seem to have a dominating role in ola nzapine biotransformation after intake of a single dose.