Stereoselective metabolism of tazofelone, an anti-inflammatory bowel disease agent, in rats and dogs and in human liver microsomes

Incubation of (R)-tazofelone and (S)-tazofelone in rat, dog, and human live r microsomes demonstrated that the (R)-tazofelone enantiomer was more rapid ly metabolized, with two diastereomeric sulfoxides as the major metabolites formed in all three species. The two diasteresomers epimerized at physiolo gical pH, therefore total sulfoxide formation rates were measured. The form ation of the total sulfoxide metabolites followed Michaelis-Menten kinetics . The K-m, V-max, and intrinsic formation clearance (V-max/K-m) values were determined in rat, dog, and human liver microsomes. The intrinsic formatio n clearance of sulfoxide from (R)-tazofelone exceeded that of (S)-tazofelon e in all three species. In vivo studies in rats and dogs dosed orally and i ntravenously confirmed the stereoselective metabolism of tazofelone observe d in vitro. Plasma concentrations of (S)-tazofelone exceeded (R)-tazofelone in rats and dogs by a factor of 3 to 4. In rat portal plasma, both enantio mers were of approximately equal concentration after oral dosing, indicatin g similar absorption. The half-lives of tazofelone and total sulfoxides in rats were 3.5 and 2.8 h, respectively. In dogs, the half-lives of tazofelon e and total sulfoxides were 2.2 and 5.5 h, respectively. Plasma clearance w as 2.3 l/h in rats and 1.4 l/h in dogs, and the volumes of distribution wer e 12 and 4.5 l, respectively, in rats and dogs. Both enantiomers were highl y bound to plasma proteins to a similar extent in both species. Chirality 1 1:233-240, 1999. (C) 1999 Wiley-Liss, Inc.