Influence of cimetidine coadministration on the pharmacokinetics of sotalol enantiomers in an anaesthetized rat model: evidence supporting active renal excretion of sotalol.
Sotalol (STL) is an amphoteric, chiral beta-adrenergic blocking drug useful in the treatment of both hypertension and ventricular arrhythmias. In the human and rat, STL enantiomers are predominantly cleared from the body by the kidney as intact drug. The renal clearance (Clr) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL enantiomers are excreted by an active renal transport system was investigated in the rat by coadministering racemic STL (10 mg kg-1) with cimetidine, 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 study period (n = 7). Blood and urine samples were collected over 6 h, during which time anaesthesia was maintained via intraperitoneal administration of pentobarbital. Cimetidine bolus and cimetidine infusion reduced STL enantiomer Clr by 43 and 59%, respectively, compared with respective saline controls. Significant stereoselectivity was observed in the cimetidine infusion group: systemic clearance, Clr (R > S), and AUC (S > R), although the magnitude of stereoselectivity was less than 5%. This study supports the hypothesis that STL enantiomers are predominantly cleared from the rat via a renal cationic transport mechanism and that this system can be competitively inhibited by the presence of cimetidine.
Carr
R A
RA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Pasutto
F M
FM
Foster
R T
RT
D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001692:Biological Transport; D002927:Cimetidine / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013015:Sotalol / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D002927:Cimetidine; D013015:Sotalol