Steady-state plasma levels of clomipramine and its metabolites: Impact of the sparteine/debrisoquine oxidation polymorphism
- 75 Downloads
After an initial placebo week, 37 depressed in-patients 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.
The results suggest that the 8-hydroxylation of clomipramine and of desmethylclomipramine are catalyzed by the same isozyme that oxidises sparteine, CYP2D6. The N-demethylation of clomipramine appears to be less clearly related to the activity of CYP2D6. Clomipramine appeared to cause more potent inhibition of sparteine oxidation than that seen previously with other tricyclic antidepressants.
Key wordsClomipramine, Sparteine genetic polymorphism, drug oxidation, metabolic pathway, interaction, P450 isozyme
Unable to display preview. Download preview PDF.
- Balant-Gorgia AE, Schulz P, Dayer P, Balant L, Kubli A, Hertsch C, Garrone G (1982) Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch Psych Neurol Sci 232: 215–222Google Scholar
- Brøsen K, Otton SV, Gram LF (1985) Sparteine oxidation polymorphism in Denmark. Acta Pharmacol Toxicol 57: 357–360Google Scholar
- Ciraulo DA, Barnhill J, Boxenbaum H (1985) Pharmacokinetic interaction of disulfiram and antidepressants. Clin Res Rep 142: 1373–1374Google Scholar
- Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1991) The effect of paroxetine and other specific serotonin re-uptake inhibitors on cytochrome P450IID6 activity in human liver microsomes. Br J Clin Pharmacol 32: 658P-659PGoogle Scholar
- Danish University Antidepressant Group (1986) Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 90: 131–138Google Scholar
- Danish University Antidepressant Group (1990) Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affective Disord 18: 289–299Google Scholar
- Eichelbaum M, Bertilsson L, Säwe J, Zekorn C (1982) Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin Pharmacol Ther 32: 184–186Google Scholar
- Gram LF, Bech P, Reisby N, Sylvester Jørgensen O (1981) Methodology in studies on plasma level/effect relationship of tricyclic antidepressants. In: Usdin E. (ed) Clinical Pharmacology in Psychiatry. Elsevier, New York, pp 155–171Google Scholar
- Gram LF, Kragh-Sørensen P, Bech P, Reisby N, Vestergaard P, Bolwig TG (1989) Danish University Antidepressant Group (DUAG) — A permanent independent multicenter group for improved quality in clinical testing of new antidepressants. Eur J Clin Pharmacol 36 [suppl.]: A157Google Scholar
- Gut J, Gasser R, Dayer P, Kronbach T, Catin T, Meyer UA (1984) Debrisoquine-type polymorphism of drug oxidation: purification from human liver of a cytochrome P450 isozyme with high activity for bufuralol hydroxylation. FEBS 173: 287–290Google Scholar
- Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, Fuji-Kuriyama Y, Gonzales FJ, Guengerich FP, Gunsalus IC, Johnson EF, Loper JC, Sato R, Waterman MR, Waxman DJ (1991) The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol M. 10: 1–14Google Scholar
- Reisby N, Gram LF, Bech P, Sihm F, Krautwald O, Elley J, Ortmann J, Christiansen J (1979) Clomipramine: plasma levels and clinical effects. Psychopharmacology 3: 341–351Google Scholar
- Skjelbo E, Brosen K (1992) Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol (in press)Google Scholar