DISPOSITION KINETICS OF ML-1035 SULFOXIDE ENANTIOMERS AND THE PROCHIRAL SULFIDE IN RATS

ML-1035, finyl)ethoxy]-N-[2-(diethyl-amino)ethyl]benzamide, is a sulfo xide compound and a racemic gastroprokinetic agent with a chiral cente r at the sulfur atom. We have investigated the disposition kinetics of (R)-ML-1035 sulfoxide (R) and (S)-ML-1035 sulfoxide (S) after the sin gle enantiomers and the racemic mixture were administered to rats in s eparate experiments. There was no noticeable chiral inversion after ei ther enantiomer dose. Both enantiomers were rapidly absorbed. After do sing with enantiomers or with the racemate, the resulting plasma conce ntration-time curve of R was closely parallel to that of S in both int ravenous and oral experiments, suggesting that the two enantiomers hav e approximately the same disposition kinetics. After intravenous enant iomer doses, only S underwent conversion to sulfide, suggesting that s ulfidation in the fiver is enantioselective. However, the enantioselec tive sulfidation after intravenous dosing did not introduce a differen ce in the global plasma disposition profiles between R and S, since th e reduction reaction is a minor metabolic process. Other metabolic rea ctions such as sulfonation and mono-N-desethylations were not enantios elective. After oral administration, conversion to sulfide was observe d for both enantioners, implicating the existence of a nonhepatic path way in sulfidation. Administration of a prochiral sulfide dose was ass ociated with an enantioselective sulfoxidation, in which the R/S conce ntration ratios increased as a function of time. In addition, enantiom eric interaction causing changes in pharmacokinetic parameters was obs erved after the oral racemate dose, while the interaction is negligibl e after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction. (C) 1993 Wiley-Liss, Inc.