Pharmacokinetics of acebutolol enantiomers after intravenous administration of racemate in a rat model: A dosing range comparison

Acebutolol (AC) is a chiral P-adrenergic blocking drug, possessing intrinsic sympathomimetic activity (ISA), and is useful clinically as the racemate in treating hypertension. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of AC and its major metabolite diacetolol (DC) are reported after intravenous administration of single 5, 15, 30, and 50 mg kg(-1) doses of racemate to male Sprague-Dawley rats. The mean area under the plasma concentration versus time curve (AUC) values display a linear relationship with respect to the administered dose. No statistical differences are observed in apparent volume of distribution (V-d), terminal elimination half-life (t(1/2)), total body clearance (CW, or renal clearance (Cl,) with respect to dose administered. Generally, R-S ratios for AUC following AC administration are statistically different from unity (p < 0.05). However, for the 50 mg kg(-1) doses the R-S ratio for AUC is not statistically different from one. For DC, the plasma disposition is nonstereoselective in plasma. The amount of R-DC recovered in urine, however, was greater than that of the antipode (R:S = 1.92 +/- 0.29). This study suggests that the enantiomeric disposition of intravenous AC is linear within the investigated range of 5-50 mg kg(-1) racemate in rats. (C) 1997 by John Wiley & Sons, Ltd.