Formation of chlorpromazine sulphoxide and monodesmethylchlorpromazine by microsomes of small intestine

Summary The metabolism of chlorpromazine by microsomal preparations of the small intestine from guinea pig and rat was studied. ³⁵S-chlorpromazine was incubated with these preparations in Krebs-Ringer bicarbonate buffer at 37°C. Control values were obtained by performing the assay at 0°C. The metabolites were extracted with dichloroethane and separated by TLC. In incubations with intestinal microsomes from guinea pigs chlorpromazine sulphoxide and monodesmethyl chlorpromazine were identified as main metabolites. The apparent Michaelis constant for sulphoxidation of chlorpromazine is approximately 20–30 M and for N-demethylation in the range of 30–100 M.Using microsomal preparations from rat intestine, however, noteworthy formation of chlorpromazine metabolites could not be found. This observation can be explained by the fact that the cytochrome P₄₅₀ content of rat intestinal microsomes was extremely low compared with that determined in guinea pig microsomes.Preliminary reports of this study were presented at the 17th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Mainz, March 23, 1976 (Knoll et al., 1976) and at the 5th International Symposium on Medicinal Chemistry, Paris, July 19, 1976