Disposition of acamprosate in the rat: influence of probenecid

The purpose of the present study was to investigate the disposition of acamprosate (calcium bis acetyl-homotaurine) in the rat. Initially, we studied the linearity of acamprosate disposition and the fraction of acamprosate excreted unchanged in the urine of the animals. Rats received 9.3, 36.6 or 73.3 mg/kg of the drug as an intravenous bolus. 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. On average, 95% of the administered dose was excreted unchanged in the urine of the animals in the 0-6 h post-administration period indicating that renal excretion is the main elimination route for this drug. Acamprosate was also administered by the intravenous route at three different constant infusion rates (2.65, 132.5 and 530 microg/min) in order to quantify total (Cl(t)) and renal (Cl(r)) plasma clearances at steady-state conditions. The mean Cl(r) values were, respectively, 4.60+/-0.42, 4.28+/-0.52 and 4.08+/-0.67 ml/min, practically equivalent to the Cl(t) values (4.78+/-0.38, 4.51+/-0.36 and 4.21+/-0.56 ml/min), confirming that the drug is mainly eliminated via renal excretion. Moreover, Cl(r) values were clearly higher than the glomerular filtration rate (2.61+/-0.26 ml/min), 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 (33.3 or 66.6 mg/kg) prior to acamprosate administration (9.3 mg/kg). Probenecid provoked a statistically significant dose-dependent reduction in the total clearance of acamprosate (from 5.8+/-0.7 ml/min in the control group to 2.6+/-0.1 ml/min in the animals treated with 66 mg/kg of probenecid) demonstrating the existence of a tubular secretion process on the renal excretion of acamprosate in the rat.