PHARMACOKINETICS OF SINGLE ORAL AND MULTIPLE INTRAVENOUS AND ORAL-ADMINISTRATION OF ACEBUTOLOL ENANTIOMERS IN A RAT MODEL

Acebutolol (AC), is a chiral, beta-adrenergic blocking agent which pos sesses partial agonist activity and is metabolized to an equipotent ch iral metabolite, diacetolol (DC). The enantiomeric disposition of AC i s reported following racemic administration as a single oral (p.o., 50 mg kg(-1)) or as a multiple thrice daily intravenous (i.v.) or p.o. d osing for four days in male Sprague-Dawley rats (n = 6). Enantiomeric concentrations of AC and DC in plasma and urine were determined using a stereospecific HPLC assay. The bioavailabilities of R- and S-enantio mer were 0.40 and 0.39 after single dose administration of AC respecti vely. These values were increased to 0.51 and 0.53 after multiple dosi ng. Although no significant differences were found in AUC(0-infinity) after single i.v. as compared with AUC(0-tau) after multiple i.v. dosi ng of AC, the 39 and 45% increase in mean AUC(0-tau) were found after multiple p.o. dosing over the corresponding AUC(0-infinity), for the s ingle p.o. dose of AC for R- and S-enantiomer, respectively. The dispo sition of DC as well as the urinary excretion of metabolite was stereo selective in favor of R-enantiomer after oral administration of AC. Th ese results indicate that AC enantiomers have low availability and mod erate extraction through the first-pass metabolism in a rat model. The higher AUC values after p.o. multiple dosing may suggest a saturable first-pass metabolism of AC. (C) 1998 John Wiley & Sons, Ltd.