Influence of cimetidine co-administration on the pharmacokinetics of acebutolol enantiomers and its metabolite diacetolol in a rat model: the effect of gastric pH on double-peak phenomena

Acebutolol (AC) is a chiral beta-adrenergic receptor-blocking agent, which has been shown to be clinically effective in hypertension. The plasma concentration-time profiles of AC exhibit two peaks following oral administration of racemate for both Rand S-enantiomers. In the present study. the absorption of AC after a single dose was Studied as a function of gastric pH in male Sprague-Dawley rats. Furthermore, the effect of cimetidine (CIM) on pharmacokinetic parameters of AC and its metabolite diacetolol (DC) was evaluated. CIM (50 mg kg(-1)) was administered via jugular vein 30 min prior to AC administration to elevate the intragastric pH. AC (50 mg kg(-1)) was administered orally by gavage and serial blood samples were collected before and for 8 h after AC administration. Plasma samples were assayed for AC and DC, pharmacokinetic parameters ere estimated and compared with those of control. The concentration-time profiles and the pharmacokinetics of AC ere unchanged after co-administration of CIM. The oral absorption of AC. as assessed by the area under the plasma concentration-time curve (AUC) and the amount Of Unchanged drug recovered in the Urine were not affected by CIM. The amount of metabolite recovered in the urine and the rate of absorption, however were significantly altered. These are unlikely to be of clinically importance as e ha c found that the extent of absorption vas not changed. We, therefore, concluded that intragastric elevation of pH has no effect either on generation of multiple peaking or on pharmacokinetic parameters of AC. (C) 2003 Elsevier Science B.V. All rights reserved.