INFLUENCE OF CIMETIDINE COADMINISTRATION ON THE PHARMACOKINETICS OF SOTALOL ENANTIOMERS IN AN ANESTHETIZED RAT MODEL - EVIDENCE SUPPORTING ACTIVE RENAL EXCRETION OF SOTALOL

Sotalol (STL) is an amphoteric, chiral beta-adrenergic blocking drug u seful in the treatment of both hypertension and ventricular arrhythmia s. In the human and rat, STL enantiomers are predominantly cleared fro m the body by the kidney as intact drug. The renal clearance (Cl-r) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL en antiomers are excreted by an active renal transport system was investi gated in the rat by coadministering racemic STL (10 mg kg(-1)) with ci metidine, an inhibitor of renal tubular secretion of organic cations. To compare the effects of short-term and sustained cimetidine exposure on STL enantiomer disposition, cimetidine was administered either as a single bolus (30 mg kg(-1), n=7) immediately prior to the STL dose, or as a 30 mg kg(-1) bolus plus a 50 mg kg(-1) infusion over the 6 h s tudy period (n=7). Blood and urine samples were collected over 6 h, du ring which time anaesthesia was maintained via intraperitoneal adminis tration of pentobarbital. Cimetidine bolus and cimetidine infusion red uced STL enantiomer Cl-r by 43 and 59%, respectively, compared with re spective saline controls. Significant stereoselectivity was observed i n the cimetidine infusion group: systemic clearance, Cl-r (R>S), and A UC (S>R), although the magnitude of stereoselectivity was less than 5% . This study supports the hypothesis that STL enantiomers are predomin antly cleared from the rat via a renal cationic transport mechanism, a nd that this system can be competitively inhibited by the presence of cimetidine.