Is there any documentation for pharmacokinetic interaction between risperidone and buspirone or bet

Fråga: Is there any documentation for pharmacokinetic interaction between risperidone and buspirone or between risperidone and citalopram?

Background: A 50-year old schizophrenic patient treated with risperidone (Risperdal) 6 mg/day suffers from anxiety and restlessness. Addition of either buspirone (Buspar) or citalopram (Cipramil) is being considered.

Sammanfattning: There is no documentation in the literature of an interaction between risperidone and buspirone or between risperidone and citalopram. However, on theoretical grounds, a metabolic interaction between risperidone and citalopram is possible. Due to lack of information concerning the metabolism of buspirone, we cannot predict any specific interaction between risperidone and buspirone.

Svar: Risperidone is a newly registered benzisoxazole derivative which shows high affinity for central serotonergic 5-HT-2, adrenergic alpha-1 and dopaminergic D-2-receptors (1,2). Risperidone is metabolized to 9-hydroxyrisperidone by the polymorphic debrisoquine hydroxylase, CYP 450 2D6 (3). Risperidone and its metabolite 9-hydroxyrisperidone are both active (3). In extensive metabolizers, the active moiety is composed of both risperidone and 9-hydroxyrisperidone, whereas risperidone is the predominant species in poor metabolizers (4).

Buspirone, an azaspirodecanedione compound which acts as 5HT-1A partial agonist, is a novel agent that has effects on anxiety with less potential for abuse than benzodiazepine (5). Buspirone is metabolized primarily by oxidation, producing hydroxylated derivatives and a pharmacologically active metabolite, 1-(2-pyrimidinyl)piperazine (1-PP) (6,7). No data is available concerning the specific enzymes catalyzing the metabolism of buspirone (8). In a report of an interaction between buspirone and haloperidol, haloperidol Cmax and AUC values were increased 30 and 50 per cent on the combination treatment (8). The enzyme involved in this interaction is not known. No reports of interactions between risperidone and buspirone have been found in the literature. Due to lack of information on the relative inhibitory characteristics of risperidone and buspirone, the risk of interaction between these two drugs cannot be predicted.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI), which is thought to act as an antidepressant through its ability to inhibit presynaptic serotonin reuptake in the brain (9). Citalopram is N-demethylated to desmethylcitalopram and didesmethylcitalopram (10). The citalopram elimination partially depends on the mephenytoin oxygenase, CYP450 2C19 (10). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the CYP2D6. Therefore, both the debrisoquine and the mephenytoin oxidation polymorphisms appear to contribute partially to the total pharmacokinetic variability of citalopram (10,11). Citalopram and desmethylcitalopram are further suggested to be relatively weak inhibitors of CYP-mediated drug oxidations in vitro (9,10). As both risperidone and desmethylcitalopram are metabolized by CYP2D6, a kinetic interaction at this level is theoretically possible. No reports concerning an interaction between risperidone and citalopram have, however, been documented in the literature. 1 Livingston MG: Resperidone. Lancet 1994; 343: 457-460 2 Kane JM: Newer antipsychotic drugs; A review of their pharmacology and therapeutic potential. Drugs 1993; 46: 585-593 3 Heykants J, Huang ML, Mannens G, Meuldermans W, Snoeck E, Beijsterveldt LV, Peer AV, Woestenborghs R: The pharmacokinetics of risperidone in humans: A summary. J Clin Psychiatry 1994; 55(suppl): 13-17 4 Huang ML, Peer AV, Woestenborghs RW, Coster RD, Heykants J, Jansen AAI, Zylicz Z, Visscher HW, Jonkman JHG: Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257-68 5 Brentano, CF: Topics in clinical pharmacology: Buspirone: A new nonbenzodiazepine anxiolytic agent. Am J Med Sci 1989; 297: 49-52 6 Gammans RE, Mayol RF, LaBudde JA. Metabolism and disposition of buspirone. Am J Med 1986; 80(suppl 3B): 41-51 7 Jajoo HK, Mayol RF, LaBudde JA, Blair IA: Metabolism of the antianxiety drug buspirone in human subjects. Drug Metabol Dispos 1989; 17: 634-640 8 Buch,AB, Harken DRV, Seidehamel RJ, Barbhaiya RH: A study of pharmacokinetic interaction between buspirone and alprazolam at steady state. J Clin Pharmacol 1993, 33: 1104-1109 9 Brosen K: The pharmacokinetics of the selective serotonin reuptake inhibitors. Clin Invest 1993; 71: 1002-1009 10 Sindrup SH, Brosen K, Hansen MGJ, Aaes-Jorgensen T, Overo KF, Gram LF: Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993; 15: 11-17 11 Drugline nr 11613 (year 1994)