Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions

1 Cisapride is a prokinetic drug that is widely used to facilitate gastroin testinal tract motility. 2 Structurally, cisapride is a substituted piperidinyl benzamide that inter acts with 5-hydroxytryptamine-4 receptors and which is largely without cent ral depressant or antidopaminergic side-effects. 3 The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P-450 (CYP) isoen zyme(s) are involved in cisapride biotransformation. Additionally, the effe cts of Various drugs on the metabolism of cisapride were investigated. 4 The major in vitro metabolite of cisapride was formed by oxidative N-deal kylation at the piperidine nitrogen, leading to the production of norcisapr ide. 5 By using competitive inhibition data, correlation studies and heterologou s expression systems, it was demonstrated that CYP3A4 was the major CYP inv olved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent. 6 The mean apparent K-m against cisapride was 8.6 +/- 3.5 mu M (n=3). The p eak plasma levels of cisapride under normal clinical practice are approxima tely 0.17 mu M; therefore it is unlikely that cisapride would inhibit the m etabolism of co-administered drugs. 7 In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs an unlikely to have a clinically relevant interaction: however, the antidep ressant nefazodone, the macrolide antibiotic troleandomycin, the HIV-1 prot ease inhibitors ritonavir and indinavir and the calcium channel blocker mib efradil inhibited the metabolism of cisapride and these interactions are li kely to be of clinical relevance. Furthermore, the antimycotics ketoconazol e, miconazole, hydroxy-itraconazole, itraconazole and fluconazole, when adm inistered orally or intravenously, would inhibit cisapride metabolism.