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 int rinsic sympathomimetic activity (ISA), and is useful clinically as the racemate in treating hypertension. Utilizing a stereospecific high-pe rformance liquid chromatographic (HPLC) assay, the enantiomeric dispos ition of AC and its major metabolite diacetolol (DC) are reported afte r intravenous administration of single 5, 15, 30, and 50 mg kg(-1) dos es of racemate to male Sprague-Dawley rats. The mean area under the pl asma concentration versus time curve (AUC) values display a linear rel ationship with respect to the administered dose. No statistical differ ences are observed in apparent volume of distribution (V-d), terminal elimination half-life (t(1/2)), total body clearance (CW, or renal cle arance (Cl,) with respect to dose administered. Generally, R-S ratios for AUC following AC administration are statistically different from u nity (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 dispo sition is nonstereoselective in plasma. The amount of R-DC recovered i n urine, however, was greater than that of the antipode (R:S = 1.92 +/ - 0.29). This study suggests that the enantiomeric disposition of intr avenous AC is linear within the investigated range of 5-50 mg kg(-1) r acemate in rats. (C) 1997 by John Wiley & Sons, Ltd.