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A comparative study on the in vitro metabolism of cisapride using subcellular liver fractions of dog, rabbit, and male and female rats
Author(s) -
Lavrijsen Karel L. M.,
Meuldermans Willem,
Knaeps Fons A. G.,
Lauwers William,
Heykants Jozef
Publication year - 1986
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430080131
Subject(s) - microsome , hydroxylation , metabolism , chemistry , cisapride , biochemistry , in vitro , drug metabolism , cytochrome p450 , phenobarbital , metabolite , high performance liquid chromatography , biotransformation , sulfation , pharmacology , chromatography , biology , enzyme
Cisapride‐ 3 H, labeled at the fluorophenyl moiety or at the piperidine ring, was incubated with the supernatant and microsomal fractions of various animal livers and an NADPH‐generating system. The major metabolites were identified by co‐chromatography with high performance liquid chromatography (HPLC) and by mass spectrometry. A mass balance of the major metabolites in incubates was made up by radio‐HPLC. The rate of metabolism of the drug decreased in the following order: rabbit ≥ male rat ≥ dog ≥ female rat. The major in vitro metabolic pathways in the animal species were rather similar. Main biotransformation routes were oxidative N ‐dealkylation at the piperidine nitrogen and aromatic hydroxylation occurring either at the fluorophenyl or at the benzamide moiety. Hydroxylation was relatively more abundant in female compared to male rats, whereas oxidative O ‐dealkylation was important in incubates with rabbit subcellular fractions only. Furthermore, the formation of at least four sulfate conjugates could be demonstrated. Metabolism experiments with phenobarbital‐induced or 3‐methylcholanthrene‐induced microsomes indicated that phenobarbital inducible cytochrome P‐450 isoenzyme(s) are involved in the in vitro metabolism of cisapride.