RENAL, BILIARY AND INTESTINAL CLEARANCE OF SOTALOL ENANTIOMERS IN RAT MODEL: EVIDENCE OF INTESTINAL EXSORPTION

Biliary clearance (Cl b ) of sotalol (STL) enantiomers was assessed in anaesthetized Sprague-Dawley rats (419±9g, mean±SEM, n=4) following administration of a 10 mg kg -1 IV dose of the racemate. Cl b for S- and R-STL (0.0675±0.0090 and 0.0662±0.0089 mL min -1 kg -1 , respectively) represented approximately 0.3% of systemic clearance (Cl s ) values for S- and R-STL (20.4±2.2 and 20.7±2.0 mL min -1 kg -1 , respectively). Bile :plasma concentration ratios at 1, 2, and 3h post-dose were approximately 1.4, 1.3, and 1.2 for both STL enantiomers. Renal clearance (Cl r ) and intestinal clearance (Cl i ) of STL enantiomers were assessed in conscious Sprague-Dawley rats (325 g, n = 4) following administration of a 10 mg kg -1 IV dose of the racemate. STL enantiomers were predominantly eliminated intact in the urine : Cl r for S- and R-STL (26.3±3.2 and 28.7±4.2 mL min -1 kg -1 , respectively) accounted for approximately 96% of CI, for S- and R-STL (27.5±3.3 and 29.9±4.2 mL min -1 kg -1 , respectively). Approximately 4% of the dose was recovered in the faeces, corresponding to Cl i values of 1.16±0.17 and 1.26±0.19 mL min -1 kg -1 for S- and R-STL, respectively. Total recovery of the administered dose in urine and faeces was 99.7±0.2 and 99.8±0.5% for S- and R-STL, respectively. It is concluded from these results in the rat model that (i) STL enantiomers are predominantly eliminated intact in urine ; (ii) STL enantiomers are excreted intact in bile, and to a much larger extent in the faeces, thus suggesting the presence of intestinal exsorption of STL ; (iii) STL does not appear to be metabolized ; and (iv) Cl s , Cl r , Cl b , and Cl i are negligibly stereoselective.