Summary
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.
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Balant-Gorgia AE, Balant LP, Genet Ch, Dayer P, Aeschlimann JM, Garrone G (1986) Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentration of clomipramine and its major metabolites. Eur J Clin Pharmacol 31: 449–455
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: 215–222
Bertilsson L, Åberg-Wistedt A (1983) The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. Br J Clin Pharmacol 15: 388–390
Brøsen K (1990) Recent developments in hepatic drug oxidation: implications for clinical pharmacokinetics. Clin Pharmacokinet 18: 220–239
Brøsen K, Gram LF (1988) First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 43: 400–406
Brøsen K, Gram LF (1989) Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 36: 537–547
Brøsen K, Klysner R, Gram LF, Otton SV, Bech P, Bertilsson L (1986a) Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 30: 679–684
Brøsen K, Otton SV, Gram LF (1985) Sparteine oxidation polymorphism in Denmark. Acta Pharmacol Toxicol 57: 357–360
Brøsen K, Otton SV, Gram LF (1986b) Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 40: 543–549
Brøsen K, Zeugin T, Meyer UA (1991) Role of P450IID6, the target of the sparteine/debrisoquine oxidation polymorphism, in the metabolism of imipramine. Clin Pharmacol Ther 49: 609–617
Ciraulo DA, Barnhill J, Boxenbaum H (1985) Pharmacokinetic interaction of disulfiram and antidepressants. Clin Res Rep 142: 1373–1374
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-659P
Danish University Antidepressant Group (1986) Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 90: 131–138
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: 289–299
Eichelbaum M, Bertilsson L, Säwe J, Zekorn C (1982) Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin Pharmacol Ther 32: 184–186
Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: A new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187
Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17: 102–105
Gram LF (1977) Plasma level monitoring of tricyclic antidepressant therapy. Clin Pharmacokinet 2: 237–251
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 155–171
Gram LF, Brosen K, Kragh-Sørensen P, Christensen P (1989) Steady-state plasma levels of E- and Z-10-OH-nortriptyline in nortriptyline-treated patients: Significance of concurrent medication and the sparteine oxidation phenotype. Ther Drug Monit 11: 508–514
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.]: A157
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: 287–290
Mellström B, Bertilsson L, Träskman L, Rollins D, Åsberg M, Sjöqvist (1979) Intraindividual similarity in the metabolism of amitriptyline and clomipramine in depressed patients. Pharmacology 19: 282–287
Mellström B, Bertilsson L, Lou Y-C, Säwe J, Sjöqvist F (1983) Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 34: 516–520
Mellström B, Bertilsson L, Säwe J, Schulz HU, Sjöqvist F (1981) E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 30: 189–193
Mellström B, Säwe J, Bertilsson L, Sjögvist F (1986) Amitriptyline metabolism: association with debrisoquine hydroxylation in nonsmokers. Clin Pharmacol Ther 39: 369–371
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: 1–14
Otton SV, Inaba T, Kalow W (1983) Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs. Life Sci 32: 795–800
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: 341–351
Sindrup SH, Gram LF, Skjold T, Grodum E, Brosen K, Beck-Nielsen H (1990) Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind crossover study. Br J Clin Pharmacol 30: 683–691
Skjelbo E, Brosen K (1992) Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol (in press)
Skjelbo E, Brøsen K, Hallas J, Gram LF (1991) The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 49: 18–23
Spina E, Birgersson C, von Bahr C, Ericsson Ö, Mellström B, Steiner E, Sjögvist F (1984) Phenotypic consistency in hydroxylation of desmethylclomipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther 36: 677–682
Syvählahti EKG, Lindberg R, Kallio J, de Vocht M (1986) Inhibitory effects of neuroleptics on debrisoquine oxidation in man. Br J Clin Pharmacol 22: 89–92
Träskman L, Åsberg M, Bertilsson L, Cronholm B, Mellström B, Neckers LM, Sjögvist F, Thorén P, Tybring G (1979) Plasma levels of clomipramine and its demethyl metabolites during treatment of depression. Clin Pharmacol Ther 26: 600–610
Vandel B, Vandel S, Jounet JM, Allers G, Volmat R (1982) Relationship between the plasma concentration of clomipramine and desmethylclomipramine in depressive patients and the clinical response. Eur J Clin Pharmacol 22: 15–20
Vinks A, Inaba T, Otton SV, Kalow W (1982) Sparteine metabolism in Canadien Caucasians. Clin Pharmacol Ther 31: 23–29
Woolhouse NM, Adjepon-Yamoah KK, Mellström B, Hedman A, Bertilsson L, Sjöqvist F (1984) Nortriptyline and debrisoquine hydroxylation in Ghanaian and Swedish subjects. Clin Pharmacol Ther 36: 374–378
Zanger UM, Vilbois F, Hardwick J, Meyer UA (1988) Absence of hepatic cytochrome P450bufl causes genetically deficient debrisoguine oxidation in man. Biochemistry 27: 5447–5454
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Steering committee: Per Bech, Tom G. Bolwig, Lars E Gram (chairman), Per Kragh Sørensen, Niels Reisby and Per Vestergaard
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Kramer Nielsen, K., Brøsen, K., Gram, L.F. et al. Steady-state plasma levels of clomipramine and its metabolites: Impact of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 43, 405–411 (1992). https://doi.org/10.1007/BF02220617
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DOI: https://doi.org/10.1007/BF02220617