Stereoselective absorption and hydrolysis of cefuroxime axetil diastereomers using the Caco-2 cell monolayer model.

Cefuroxime axetil, the orally active prodrug of cefuroxime is marketed as a 1:1 mixture of two diastereomers designated as R (1'R, 6R, 7R) and S (1'S, 6R, 7R). Prodrug hydrolysis is thought to occur during intestinal absorption, however little is known concerning the relative availability of cefuroxime from each isomeric form. The Caco-2 cell monolayer model was used to examine the possible stereoselectivity of absorption by measuring the accumulation and epithelial transport rate in the apical to basolateral direction of cefuroxime and cefuroxime axetil following application of the mixture (1.0 mM) or individual diastereomers (0.5 mM0 of cefuroxime axetil. Cefuroxime appearance in the basolateral chamber was in the order: mixture > R > S following application of the prodrug. The accumulation of unchanged cefuroxime axetil was S > R irrespective of the form applied, i.e. individual diastereomer or the mixture. Such stereoselective differences in both absorption and/or hydrolysis may contribute to the observed oral bioavailability (30-50%) of cefuroxime in vivo.

Pregnancy alterations following xenobiotic-induced delays in ovulation in the female rat.

Chlordimeform [N'-(4-chloro-o-tolyl)-N,N-dimethylformamidine] has been shown to cause a 1-day delay in the surge of luteinizing hormone (LH) in ovariectomized, steroid-primed female rats, presumably through its ability to block CNS alpha-noradrenergic receptors and consequently CNS regulation of anterior pituitary function. In the present study, we determined whether a chlordimeform-induced delay in the ovulatory surge of LH would alter pregnancy outcome in intact females. Chlordimeform (50 mg/kg) or sodium pentobarbital (35 mg/kg), as a positive control, was administered in order to delay ovulation 24 (1-day delay) or 48 hr (2-day delay). Females were then housed with proven fertile males on the evening of proestrus (0-day delay group), the following evening (1-day delay group), or the evening after that (2-day delay group). The number of receptive females in each group, the mean lordosis quotient, and the number of sperm-positive females in each group were recorded. All females were killed on Gestation Day 20. The number of pregnant females in the 1- or 2-day delay groups was reduced with both chlordimeform and pentobarbital. Also, delaying ovulation for 1 or 2 days with either compound resulted in a significant reduction in the number of live pups present on Gestation Day 20 and a decrease in the number of implantation sites. Litter size was not affected if the females were mated on the same day that treatment was administered (0-day delay).(ABSTRACT TRUNCATED AT 250 WORDS)