STEADY-STATE CONCENTRATIONS OF THE ENANTIOMERS OF MIANSERIN AND DESMETHYLMIANSERIN IN POOR AND IN HOMOZYGOUS AND HETEROZYGOUS EXTENSIVE METABOLIZERS OF DEBRISOQUINE

Steady state concentrations of (S)- and (R)-mianserin and desmethylmia nserin were measured in 21 homozygous extensive metabolizers (as deter mined by genotyping for mutations 3 [or A] and 4 [or B]), in seven het erozygous extensive metabolizers and in one poor metabolizer of debris oquine, as well as in one patient receiving very high doses of mianser in (360 mg/day) and fluoxetine (160 mg/day), a strong cytochrome P450I ID6 inhibitor. The mean dose of mianserin was (mean +/- SD, range: 67 +/- 63, 10 to 360 mg/day). High dispersions of the (S)/(R)-mianserin a nd desmethylmianserin ratios were observed (mean +/- SD, range: 2.10 /- 1.01, 0.64 to 4.76, and 0.29 +/- 0.14, 0.08 to 0.57, respectively). The highest (S)/(R)-mianserin ratio was calculated for the poor metab olizer (4.76) agreeing with those results of a single-dose study with poor and extensive metabolizers of debrisoquine, in that the cytochrom e P450IID6 is probably involved in the metabolism of mianserin with an enantioselectivity for the (S)-enantiomer. Nevertheless, the mean con centration-to-dose ratios for (S)- or (R)-mianserin or desmethylmianse rin were not significantly different between homozygous and heterozygo us extensive metabolizers, and no particular values were measured in t he poor metabolizer nor in the patient receiving fluoxetine. Furthermo re, the (S)/(R)-mianserin ratio measured in the PM was only slightly h igher than the second highest ratio (3.85) of an homozygous extensive metabolizer, whereas no particular value (2.92) was calculated for the patient taking fluoxetine. Finally, no significant differences in (S) /(R)-mianserin or (S)/(R)-desmethylmianserin were calculated between h omozygous and heterozygous extensive metabolizers. Although the number of patients included in this study is too low to allow definite concl usions, the results suggest that the debrisoquine genotype has only a moderate influence on the steady state concentrations of the enantiome rs of mianserin and desmethylmianserin.