Olanzapine (OL), an antipsychotic, is metabolized to N-desmethyl olanzapine (OL-d) by CYP1A2 in vitro. Smoking induces CYP1A2 and smokers have higher OL clearance (CL). This study evaluated the effect of fluvoxamine (FL), a potent CYP1A2 inhibitor, on OL PK and PD in ten healthy male smokers. FL (from 50 to 100 mg) or placebo (PL) were administered for 11 days. Beginning on the fourth day OL (from 2.5 to 7.5 mg) was administered for 8 days. During the first 4 days of OL-FL treatment, somnolence was increased 19-115 % over OL-PL. Volunteers accommodated to somnolence effects which returned to baseline after 4 days. FL increased the mean OL Cmax 84 % from 10.1 ng/ml and AUC0-24 119 % from 1.6 kg*hr/L. FL decreased OL CL and Vdss 50 % from 57.1 L/hr and 45 % from 28.4 L/kg, respectively. FL decreased the mean OL-d Cmax 64 % from 2.2 ng/ml and AUC0-24 77 % from 0.4 kg*hr/L OL and OL-d T1/2 did not change. These data confirm that CYP1A2 metabolizes OL to OL-d in vivo. Apparently, FL co-administration with OL results in statistically significant decreases in OL CL by FL inhibiting OL CYP1A2 first-pass metabolism resulting in statistically significant higher OL and lower OL-d plasma concentrations.
|Original language||English (US)|
|Number of pages||1|
|Journal||Clinical Pharmacology and Therapeutics|
|State||Published - Dec 1 1997|
ASJC Scopus subject areas
- Pharmacology (medical)