Abstract
Background
In vitro findings have indicated that the novel anxiolytic drug, deramciclane, is an inhibitor of the cytochrome P 450 (CYP) 2D6 enzyme and co-administration of deramciclane and the CYP2D6 probe drug desipramine is possible in clinical practice.
Objective
To evaluate the effects of deramciclane on CYP2D6 activity as measured by desipramine pharmacokinetics and pharmacodynamics using paroxetine as a positive control for CYP2D6 inhibition.
Methods
Fifteen healthy subjects received either 60 mg deramciclane, 20 mg paroxetine or matched placebo for 8 days in randomized order in this double-blind, cross-over study. On day 8 of each study phase, the subjects received a 100-mg single dose of desipramine. Desipramine and its CYP2D6-dependent metabolite, 2-OH-desipramine, concentrations were measured for 240 h. Measurement of secretion of saliva, Visual Analogue Scale assessment of dryness of mouth and tiredness were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane or paroxetine co-administration with desipramine.
Results
Repeated administration of deramciclane doubled the AUC of desipramine (P<0.001), while paroxetine caused a 4.8-fold increase in the AUC of desipramine (P<0.001). Significant correlations were observed with paroxetine (rs=0.84, P<0.001) and deramciclane (rs=0.51, P=0.0498) concentrations and the magnitude of increase of desipramine AUC. Both deramciclane and paroxetine decreased the formation of 2-OH-desipramine in the first-pass phase. The AUC ratio of 2-OH-desipramine/desipramine was decreased by 39% (P<0.001) by deramciclane and by 74% (P<0.001) by paroxetine. There were no changes in the secretion of saliva during co-administration of desipramine with deramciclane compared with placebo.
Conclusion
Although deramciclane seems to be a weaker inhibitor of CYP2D6 than paroxetine, dose adjustment of drugs metabolized by CYP2D6 may be needed when used concomitantly with deramciclane.
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References
Alderman J, Preskorn SH, Greenblatt DJ, Harrison W, Penenberg D, Allison J, Chung M (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 17:284–291
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, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993a) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44:349–355
Brøsen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S (1993b) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45:1211–1214
Christensen M, Tybring G, Mihara K, Yasui-Furokori N, Carrillo JA, Ramos SI, Andersson K, Dahl ML, Bertilsson L (2002) Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther 71:141–152
Dahl ML, Iselius L, Alm C, Svensson JO, Lee D, Johansson I, Ingelman-Sundberg M, Sjoqvist F (1993) Polymorphic 2-hydroxylation of desipramine. A population and family study. Eur J Clin Pharmacol 44:445–450
Gacsalyi I, Gigler G, Szabados T, Kovacs A, Vasar E, Männistö PT (1996) Different antagonistic activity of deramciclane (EGIS-3886) on peripheral and central 5-HT2 receptors. Pharm Pharmacol Lett 6:82–85
Hägg S, Spigset O, Dahlqvist R (2001) Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 51:169–173
Kanerva H, Kilkku O, Heinonen E, Helminen A, Rouru J, Tarpila S, Scheinin M, Huupponen R, Klebovich I, Drabant S, Urtti A (1999a) The single-dose pharmacokinetics and safety of deramciclane in healthy male volunteers. Biopharm Drug Dispos 20:327–334
Kanerva H, Kilkku O, Helminen A, Rouru J, Scheinin M, Huupponen R, Klebovich I, Drabant S, Urtti A (1999b) Pharmacokinetics and safety of deramciclane during multiple oral dosing. Int J Clin Pharmacol Ther 37:589–597
Kanerva H, Vilkman H, Någren K, Kilkku O, Kuoppamaki M, Syvalahti E, Hietala J (1999c) Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration—a positron emission tomography study. Psychopharmacology 145:76–81
Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R (2000) Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology 147:378–383
Madsen H, Enggaard TP, Hansen LL, Klitgaard NA, Brøsen K (2001) Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide. Clin Pharmacol Ther 69:41–47
Naukkarinen H (2001) Deramciclane in the treatment of patients with generalized anxiety disorder: a randomized, double-blind, placebo controlled, dose-finding study. Eur Neuropsychopharmacol 11[Suppl]:S301
Neliat G (2000) Study on N-desmethylderamciclane fumarate in various receptor binding assays (study report 4474a). CEREB (Department 1–410), Le Bois l’Eveque, Celle l’Evescault, France
Pälvimäki EP, Majasuo H, Kuoppamäki M, Männistö PT, Syvälahti E, Hietala J (1998) Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation. Psychopharmacology 136:99–104
Rowland M, Tozer TN (1995) Metabolite kinetics. In: Rowland M, Tozer TN (eds) Clinical pharmacokinetics. Concepts and applications. Lippincott, Williams and Wilkins, Philadelphia, pp 367–393
Spina E, Pollicino AM, Avenoso A, Campo GM, Perucca E, Caputi AP (1993) Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 15:243–246
Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E (1995) The effect of carbamazepine on the 2-hydroxylation of desipramine. Psychopharmacology 117:413–416
Spina E, Avenoso A, Campo GM, Caputi AP, Perucca E (1996) Phenobarbital induces the 2-hydroxylation of desipramine. Ther Drug Monit 18:60–64
Swanson JR, Jones GR, Krasselt W, Denmark LN, Ratti F (1997) Death of two subjects due to imipramine and desipramine metabolite accumulation during chronic therapy: a review of the literature and possible mechanisms. J Forensic Sci 42:335–339
Acknowledgement
This study was sponsored by Orion Pharma.
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Laine, K., De Bruyn, S., Björklund, H. et al. Effect of the novel anxiolytic drug deramciclane on cytochrome P 450 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol 59, 893–898 (2004). https://doi.org/10.1007/s00228-003-0714-z
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DOI: https://doi.org/10.1007/s00228-003-0714-z