Estudios farmacocinéticos y biofarmacéuticos del acamprosato en la rata.

Abstract

Acamprosate is a drug used in relapse prevention of alcoholism. The purpose of the present study was to investigate the mechanisms involved in the absorption and elimination of this drug in the rat. In order to study the linearity of acamprosate disposition, rats received 2.8, 11 or 22 mg of the drug as an intravenous bolus. Moreover, acamprosate was perfused by the intravenous route at three different constant infusion rates (2.65, 132.5 and 530.0 µg/min). The statistical analysis of the pharmacokinetic parameters did not reveal any significant difference, indicating that acamprosate disposition was linear within the range of the doses assayed. Relating to its elimination, the obtained results indicated that the administered dose was excreted unchanged and exclusively by renal route( = 95.0 ± 13.9%). Moreover, values were clearly higher than the glomerular filtration rate, suggesting the existence of a highly efficient tubular secretion mechanism in the renal excretion of the drug. To confirm this hypothesis, two groups of rats were intravenously treated with probenecid (10 or 20 mg) prior to acamprosate administration. Probenecid provoked a statistically significant (p<0.001) dose-dependent increase in mean plasma levels of acamprosate, demonstrating the existence of a tubular secretion process on the renal excretion of acamprosate in the rat. The acamprosate bioavailability in rats, estimated after the oral administration of 2.8 or 22 mg of the drug, was around 20 %. The statistical analysis reveal the existence of differences among the values estimated after oral and intravenous administration.This fact suggests the existence of a flip-flop phenomenon involved in acamprosate pharmacokinetics after oral administration. We perfused an isotonic solution of acamprosate (560 µg/ml) in the proximal, middle or distal segment of the small intestine of the animals. The topographic study of acamprosate absorption in the rat revealed non-significant differences among values tested. So, there is not a preferent zone in the acamprosate intestinal absorption in the rat and, probably, this low value is responsible for the low bioavailability of the drug after oral administration. Finally, we made an attempt to improve acamprosate bioavailability through the modulation of its intestinal absorption with several enhancers using in situ, in vitro and in vivo models. Only sodium caprate (C10) was able to increase the of acamprosate and the apparent permeability ( ) obtained in Caco-2 cells (around 2-fold). However, the drug bioavailability in rats (around 20%) did not improve in presence of any of the C10 concentration tested. It is concluded that acamprosate absorption occurs likely via paracellular pathway and can be enhanced by sodium caprate in situ and in vitro but not in vivo