An antibiotic interaction with ethinyloestradiol in the rat and rabbit

Abstract

When bile containing conjugates of the synthetic oestrogen ethinyloestradiol (EE 2) was incubated with rat intestinal contents it was found that the duodenum and upper small intestine caused negligible breakdown. Further down the intestine, lower small intestine and caecum, there was appreciable breakdown with 14.13 ± 9.01 and 71.0 ± 7.58% of the conjugates hydrolysed respectively. When rats were pretreated with ampicillin (200 mg/kg/day for 4 days), there was a clear loss of deconjugating capacity by the gut contents from aboral regions of the gut. When EE 2 conjugates were infused into the caecum of “recipient” rats, 32.6 ± 2.3% of the infusate was excreted into the bile in 6 h. Pretreatment of “recipient” rats with ampicillin or neomycin (200 mg/kg/day for 4 days) or neomycin + lincomycin (100 + 100 mg/kg/day for 4 days) or cefoxitin (100 mg/kg/day for 4 days) significantly reduced ( P < 0.001) the amount of steroid appearing in bile. 8.1 ± 2.5, 12.4 ± 2.1, 6.9 ± 1.7 and 6.2 ± 1.3% of the infusate was excreted in bile in rats pretreated with ampicillin, neomycin, neomycin + lincomycin and cefoxitin respectively. There was a correlation between the reduction in enterohepatic circulation (EHC) and suppression of the gut flora. Following intravenous administration of EE 2 to either rats or rabbits, there was a biphasic decline in the plasma concentration. In rats, at 5 h, and in rabbits, at approximately 8 h, there was a secondary peak of plasma EE 2 concentration which was consistent with EHC of the steroid. Pretreatment of rabbits with neomycin + lincomycin caused a reduction in the secondary peak from 0.84 ± 0.46 to 0.11 ± 0.06 ng/ml. In addition, there was an overall decrease in the disposition of EE 2, such that the area under the curve (AUC 0–12h) declined from 61.3 ± 6.2 to 37.4 ± 5.3 ng/ml/h. Plasma clearance was significantly increased by antibiotic treatment from 2.83 ± 0.21 to 4.45 ± 0.68 ml/min/100 g b.wt. It is suggested that this may result from either increased hepatic uptake or intestinal secretion of EE 2.