EFFECTS OF THIORIDAZINE, AN INHIBITOR OF CYP2D6, ON THE STEADY-STATE PLASMA-CONCENTRATIONS OF THE ENANTIOMERS OF MIANSERIN AND ITS ACTIVE METABOLITE, DESMETHYLMIANSERIN, IN DEPRESSED JAPANESE PATIENTS

The antidepressant mianserin is administered as a racemate of the S(+) - and R(-)-enantiomers. Previous in-vitro studies have suggested that CYP2D6 is involved in the stereoselective metabolism of mianserin and its active metabolite, desmethylmianserin. To determine a role for (CY P2D6 in vivo, the effects of thioridazine, an inhibitor of CYP2D6, on the steady-state plasma concentrations of the enantiomers of mianserin and desmethylmianserin were examined in 13 depressed Japanese patient s. All patients were taking 30 mg of racemic mianserin at bedtime for 8-50 days. Thioridazine (40 mg/day) was coadministered for 1 week, and blood samplings were performed before and after thioridazine coadmini stration, 12 h after bedtime dosing, Plasma concentrations of the enan tiomers of mianserin and desmethylmianserin were measured by HPLC, and the CYP2D6 genotype was determined by allele-specific PCR analysis. T hioridazine significantly increased plasma concentration of S(+)-mians erin (mean SD:78.2+/-35.0 vs, 150.8+/-48.7 nM, P<0.001), but not R(-)- mianserin (39.8+/-21.2 vs. 39.5+/-20.6 nM, NS). Thioridazine also sign ificantly increased plasma concentrations of both S-desmethylmianserin (11.9+/-2.8 vs. 24.4+/-10.7 nhl, P<0.01) and R-desmethylmianserin (42 .6+/-28.4 vs. 115.6+/-36.9 nM, P < 0.001). One patient homozygous for the defective allele CYP2D65 had the second highest and highest plasm a concentrations of S(+)-mianserin and R-desmethylmianserin, respectiv ely, before thioridazine coadministration, and exhibited little increa se in plasma concentration of the drugs after thioridazine coadministr ation. These results suggest that thioridazine specifically inhibits t he metabolism of S(+)-mianserin and R-desmethylmianserin, probably thr ough inhibition of CYP2D6, but not R(-)-mianserin.