Dose-independent pharmacokinetics of a candidate for diabetic neuropathy, SR-4668, after intravenous and oral administration to rats: Intestinal first-pass effect.

Dose-independent pharmacokinetic parameters of SR-4668 were observed after intravenous (i.v.) administrations at doses of 25, 50, and 75 mg/kg and oral administrations at doses of 50, 100, and 150 mg/kg to rats. The hepatic, gastric, and intestinal first-pass effects of SR-4668 were also measured after i.v., intraportal (i.p.), intraduodenal (i.d.), and intragastric (i.g.) administrations at a dose of 50 mg/kg to rats. Although a considerable amount of orally administered SR-4668 was absorbed, the F was low--only 33%. This indicates considerable first-pass (gastric, intestinal, and/or hepatic) effects of SR-4668 in rats. After i.v. administrations, the total body clearances of SR-4668 were considerably slower than the reported cardiac output in rats, suggesting that the first-pass effects of SR-4668 in the lung and heart could be negligible, if any, in rats. The AUCs of SR-4668 were comparable between i.v. and i.p. administrations, suggesting that the hepatic first-pass effect of SR-4668 was not considerable in rats. The AUCs were also comparable between i.d. and i.g. administrations, suggesting that gastric first-pass effect was almost negligible in rats. However, the AUC after an i.d. administration was significantly smaller (approximately 55% decrease) than that after an i.p. administration, suggesting that the intestinal first-pass effect was approximately 55% of oral dose. The rests of the orally administered dose could be mainly due to degradation of SR-4668 in gastric juices; 77.3-95.6% of the spiked amount of SR-4668 were recovered after 4-h incubation in five human gastric juices. The above data suggested that the low F of SR-4668 could be mainly due to considerable intestinal first-pass effect in rats. Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1112-1124, 2003