Incubation of (R)-
tazofelone and (S)-
tazofelone in rat, dog, and human liver microsomes demonstrated that the (R)-
tazofelone enantiomer was more rapidly metabolized, with two diastereomeric
sulfoxides as the major metabolites formed in all three species. The two diasteresomers epimerized at physiological pH, therefore total
sulfoxide formation rates were measured. The formation of the total
sulfoxide metabolites followed Michaelis-Menten kinetics. The K(m), Vmax, and intrinsic formation clearance (Vmax/K(m)) values were determined in rat, dog, and human liver microsomes. The intrinsic formation clearance of
sulfoxide from (R)-
tazofelone exceeded that of (S)-
tazofelone in all three species. In vivo studies in rats and dogs dosed orally and intravenously confirmed the stereoselective metabolism of
tazofelone observed 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 enantiomers were of approximately equal concentration after oral dosing, indicating 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
tazofelone and total
sulfoxides were 2.2 and 5.5 h, respectively. Plasma clearance was 2.3 l/h in rats and 1.4 l/h in dogs, and the volumes of distribution were 12 and 4.5 l, respectively, in rats and dogs. Both enantiomers were highly bound to
plasma proteins to a similar extent in both species.