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

• Published in: British journal of pharmacology Vol. 129; no. 8; pp. 1655 - 1667
• Main Authors: Bohets, H, Lavrijsen, K, Hendrickx, J, Van Houdt, J, Van Genechten, V, Verboven, P, Meuldermans, W, Heykants, J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2000; Nature Publishing
• Subjects: AIDS/HIV; Anti-Ulcer Agents - metabolism; Biological and medical sciences; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Cisapride; Cisapride - metabolism; CYP2A6; CYP3A4; Cytochrome P-450 Enzyme System - metabolism; Digestive system; drug–drug interactions; human liver microsomes; Humans; in vitro; Isoenzymes - metabolism; Lentivirus; Mass Spectrometry; Medical sciences; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; norcisapride; pharmacokinetics; Pharmacology. Drug treatments; prokinetic; Human; Drug combination; Cisapride; Digestive system; Isozyme; Metabolite; Cytochrome P450; Dealkylation; Liver; Microsome; Metabolism; In vitro; Benzamide derivatives; Drug interaction; Pharmacokinetics; Antiemetic
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703246

Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility. Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5‐hydroxytryptamine‐4 receptors and which is largely without central depressant or antidopaminergic side‐effects. The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P‐450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated. The major in vitro metabolite of cisapride was formed by oxidative N‐dealkylation at the piperidine nitrogen, leading to the production of norcisapride. By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent. The mean apparent Km against cisapride was 8.6±3.5 μM (n=3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 μM; therefore it is unlikely that cisapride would inhibit the metabolism of co‐administered drugs. 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 are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV‐1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy‐itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism. British Journal of Pharmacology (2000) 129, 1655–1667; doi:10.1038/sj.bjp.0703246