Low bioavailability of amoxicillin in rats as a consequence of presystemic degradation in the intestine.

Several studies have been carried out to elucidate the causes of the low oral bioavailability of amoxicillin in rats. The hepatic first-pass effect of the antibiotic was estimated by comparing the area under the plasma drug concentration-versus-time curve from time zero to infinity (AUC0-infinity) obtained after injecting the drug into a mesenteric vein with the AUC0-infinity value obtained after injecting the drug into the jugular vein of conscious rats. No hepatic first-pass effect was detected. The bioavailability of amoxicillin after intraduodenal administration was only 51%, and the fraction of the dose remaining in the intestine at the end of the experiment was 4.5%. This was far less than the fraction that did not reach systemic circulation, which indicates a presystemic loss of drug, probably at the intestine. In vitro studies corroborated the fact that amoxicillin is subjected to presystemic degradation by intestinal juices and intestinal tissues. The greatest loss of drug occurred in the complete intestine (45% of the initial amount), and it was mainly due to the action of intestinal tissues (28% of the initial amount) but was also due to the action of intestinal juices (15% of the initial amount). The absorption of amoxicillin in three parts of the intestine (upper, middle, and lower) was also evaluated. The largest AUC0-infinity value and the highest plasma drug levels were obtained when amoxicillin absorption took place in the middle intestine. The smallest AUC0-infinity value and the lowest plasma drug levels corresponded to absorption from the upper intestine.