Abstract
The effect of carbamazepine (CBZ, 200 mg twice daily for 28 days) on the kinetics of a single oral dose of desipramine (DMI, 100 mg) was investigated in six healthy volunteers. Compared with a control session, treatment with CBZ caused a marked increase in DMI apparent oral clearance (from 1.05 ± 0.40 to 1.38 ± 0.52 1 h per kg, means ± SD,P<0.01) and a significant shortening in DMI half-life (from 22.1 ± 3.5 to 17.8 ± 3.5 h,P<0.01). The amount of 2-hydroxy-desipramine (2-OH-DMI) excreted in urine over a 24-h period was significantly increased during CBZ intake (from 75 ± 15 to 92 ± 16 µmol,P<0.01). These findings suggest that CBZ induces the 2-hydroxylation of DMI, a reaction primarily catalyzed by the polymorphic CYP2D6 isozyme. This interaction may have considerable practical significance.
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Birgersson C, Morgan ET, Jornvall H, Von Bahr C (1986) Purification of desmethylimipramine and debrisoquine hydroxylating cytochrome P-450 from human liver. Biochem Pharmacol 35:3165–3166
Brosen K (1990) Recent developments in hepatic drug oxidation. Implications for clinical pharmacokinetics. Clin Pharmacokinet 18:220–239
Brosen K, Gram LF (1989) Clinical significance of the sparteine/debrisoquin oxidation polymorphism. Eur J Clin Pharmacol 36:537–547
Brosen K, Kragh-Sorensen P (1993) Concomitant intake of nortriptyline and carbamazepine. Ther Drug Monit 15:258–260
Brown CS, Wells BG, Cold JA, Froemming JH, Self TH, Jabbour JT (1990) Possible influence of carbamazepine on plasma imipramine concentrations in children with attention deficit hyperactivity disorder. J Clin Psychopharmacol 5:359–362
Dahl ML, Bertilsson L (1993) Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 3:61–70
Eichelbaum M, Gross AS (1990) The genetic polymorphism of debrisoquine/sparteine metabolism. Clinical aspects. Pharmacol Ther 46:377–394
Eichelbaum M, Tomson T, Tybring G, Bertilsson L (1985) Carbamazepine metabolism in man. Induction and pharmacogenetic aspects. Clin Pharmacokinet 10:80–90
Eichelbaum M, Mineshita S, Ohnhaus EE, Zekorn C (1986) The influence of enzyme induction on polymorphic sparteine oxidation. Br J Clin Pharmacol 22:49–53
Gonzalez FJ, Meyer UA (1991) Molecular genetics of the debrisoquin-sparteine polymorphism. Clin Pharmacol Ther 50:233–238
Gram LF (1974) Metabolism of tricyclic antidepressants. Dan Med Bull 21:218–231
Jann MW, Ereshefsky L, Saklad SR, Seidel DR, Davis CM, Burch NR, Bowden CL (1985) Effects of carbamazepine on plasma haloperidol levels. J Clin Psychopharmacol 5:106–109
Jerling M, Bertilsson L, Sjoqvist F (1994) The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline. Ther Drug Monit 16:1–12
Leclercq V, Desager JP, Horsmans Y, van Nieuwenhuyze Y, Harvengt C (1989) Influence of rifampicin, phenobarbital and cimetidine on mixed function mono-oxigenase in extensive and poor metabolizers of debrisoquine. Int J Clin Pharmacol Ther Toxicol 27:593–598
Leinonen E, Lillsunde P, Laukkanen V, Ylitalo P (1991) Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients. J Clin Psychopharmacol 11:313–318
Llerena A, Alm C, Dahl ML, Ekvist B, Bertilsson L (1992) Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype. Ther Drug Monit 14:92–97
Perucca E, Hedges A, Makki KA, Ruprah M, Wilson JF, Richens A (1984) A comparative study of the enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol 18:401–410
Post RM, Uhde TW, Ballenger JC, Squillace KM (1983) Prophylactic efficacy of carbamazepine in manic-depressive illness. Am J Psychiatry 140:1602–1604
Schmid B, Bircher J, Preisig R, Kupfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation ofo- demethylation with debrisoquine hydroxylation. Clin Pharmacol Ther 38:618–624
Spina E, Caputi AP (1994) Pharmacogenetic aspects in the metabolism of psychotropic drugs: pharmacokinetic and clinical implications. Pharmacol Res 29:121–137
Spina E, Birgersson C, Von Bahr C, Ericsson O, Mellstrom B, Steiner E, Sjoqvist F (1984) Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther 36:677–682
Spina E, Steiner E, Ericsson O, Sjoqvist F (1987) Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 41:314–319
Spina E, Campo GM, Avenoso A, Pollicino AM, Caputi AP (1992) Effect of buspirone or zopiclone on plasma concentrations of imipramine and desipramine in depressed patients. Eur Bull Drug Res 1:37–40
Sutfin TA, Jusko WJ (1979) High-performance liquid cromatography assay for imipramine, desipramine, and their 2-hydroxylated metabolites. J Pharm Sci 68:703–705
Zanger UM, Vilbois F, Hardwick JP, Meyer UA (1988) Absence of hepatic cytochrome P450bfI causes genetically deficient debrisoquine oxidation in man. Biochemistry 27:5447–5454
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Spina, E., Avenoso, A., Campo, G.M. et al. The effect of carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology 117, 413–416 (1995). https://doi.org/10.1007/BF02246212
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DOI: https://doi.org/10.1007/BF02246212