Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism.
The pharmacokinetics of mianserin and its main metabolite desmethylmianserin were studied in poor and extensive metabolizers of debrisoquin and of S-mephenytoin after a single oral dose of racemic mianserin. The debrisoquin metabolic ratio (MR) correlated significantly with area under the serum concentration-time curves (AUC) for (+/-)-mianserin and (+/-)-desmethylmianserin. Enantioselective high-performance liquid chromatographic analysis of mianserin showed that debrisoquin MR was related to AUC(0-12) for S(+)-mianserin (rs = 0.87; p = 0.001; n = 15) but not for R(-)-mianserin. The ratio between the AUC(0-12) for S(+)-mianserin and that for R(-)-mianserin was higher in poor metabolizers than in extensive metabolizers. Two extremely rapid extensive metabolizer subjects had the lowest mianserin S/R ratios. No differences in the pharmacokinetics of mianserin or desmethylmianserin were found between extensive metabolizers and poor metabolizers of S-mephenytoin. The study shows that the elimination of both mianserin and its main metabolite desmethylmianserin is dependent on CYP2D6 activity. Furthermore, the CYP2D6-dependent elimination of mianserin shows marked enantioselectivity for the more active S(+)-enantiomer of mianserin.
Dahl
M L
ML
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Sweden.
Tybring
G
G
Elwin
C E
CE
Alm
C
C
Andreasson
K
K
Gyllenpalm
M
M
Bertilsson
L
L
D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003647:Debrisoquin / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000737:chemistry / Q000378:metabolism*; D008803:Mianserin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D013548:Sweden; D044465:White People
D008803:Mianserin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C056517:desmethylmianserin; D008617:Mephenytoin; D003647:Debrisoquin