title: Steady-state plasma levels of clomipramine and its metabolites: impact of the sparteine/debrisoquine oxidation polymorphism. Danish University Antidepressant Group.
abstract: After an initial placebo week, 37 depressed inpatients were treated with the fixed dose of 75 mg clomipramine b.d. A sparteine test was carried out during the placebo period and again during the second week of active therapy. Blood for drug assay was collected at the end of the inter-dose interval in the (morning) at weekly intervals. Clomipramine and four metabolites (desmethylclomipramine, didesmethylclomipramine, 8-hydroxyclomipramine, and 8-hydroxydesmethylclomipramine) in plasma were assayed by reversed phase HPLC. The clomipramine and desmethylclomipramine steady-state plasma levels varied by factors of 11 and 9, respectively, and the clomipramine/8-hydroxyclomipramine and desmethylclomipramine/8-hydroxydesmethylclomipramine ratios both varied by 7-fold. During the placebo week, 36 patients were phenotyped as extensive metabolizers (EM) (metabolic ratio, MR, 0.1-2.0), and one patient was phenotyped as a poor metabolizer (PM) (MR > 300). During clomipramine treatment, one patient changed phenotype from EM to PM (MR = 140). In the EM, the median of the MR increased from 0.4 to 2.3. There was a statistically significant correlation between the MR before and during clomipramine treatment, even when the PM was excluded. Neither the steady-state plasma clomipramine levels nor the clomipramine/desmethylclomipramine ratios showed a significant correlation with the MR. In contrast, the desmethylclomipramine and didesmethylclomipramine steady-state levels and the desmethylclomipramine/8-hydroxydesmethylclomipramine and clomipramine/8-hydroxyclomipramine ratios showed a significant positive correlation with the MR. The PM had the highest steady-state plasma desmethylclomipramine level and the highest desmethylclomipramine/8-hydroxydesmethylclomipramine ratio. These correlation coefficients (rs) were generally increased when the correlation analyses were based on the MR obtained during clomipramine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Clinical Pharmacology, Odense University, Denmark.
authors.forename: K K
authors.initials: KK
authors.lastname: Nielsen
authors.forename: K
authors.initials: K
authors.lastname: Brøsen
authors.forename: L F
authors.initials: LF
authors.lastname: Gram
mesh_terms: D000328:Adult; D000368:Aged; D002997:Clomipramine / Q000031:analogs & derivatives / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism*; D003863:Depression / Q000097:blood / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D013034:Sparteine / Q000378:metabolism*
chemical_list: C012273:desmethylclomipramine; D013034:Sparteine; C053390:8-hydroxyclomipramine; D003577:Cytochrome P-450 Enzyme System; D002997:Clomipramine; D003647:Debrisoquin