The effect of phenobarbital and cimetidine on the elimination kinetics and distribution in the heart and liver of propranolol in rats with acute and chronic inflammations

: Intravenous administration of propranolol (10 mg/kg) to rats with turpentine-induced inflammation and adjuvant-induced arthritis results in the reduction of the systemic clearance (Cltot.p), volume distribution (Vd,ss) and free fraction (fu). At the same time the area under the pharmacokinetic curve (AUC) increases and the half-life period (t1/2 beta) remains the same. In the phenobarbital-treated rats with acute inflammation Cltot.p increases, AUC and t1/2 beta decreased. Administration of cimetidine resulted in the opposite effect. In rats with adjuvant arthritis phenobarbital and cimetidine administration did not affect the propranolol elimination kinetics. In the phenobarbital-treated rats with inflammation Vd,ss significantly decreased and virtually did not change in cimetidine treated rats. The fu of propranolol increased markedly after the cimetidine treatment in all rats with inflammation, whereas phenobarbital treatment appeared effective only in rats with acute inflammation. The tissue-to plasma concentration ratio (Kp) of propranolol decreased in the liver of rats both with acute and chronic inflammation, whereas in the heart the effect was observed only in rats with chronic inflammation. The tissue to plasma concentration ratio of unbound propranolol (Kpu) decreased only in the liver of rats with acute inflammation. In the phenobarbital-treated rats with adjuvant arthritis Kp of propranolol in the liver increased and in the heart decreased, whereas cimetidine-treatment did not change Kp of propranolol in heart and decreased it in the liver. The Kpu of propranolol decreased only in the heart of rats with acute inflammation after phenobarbital treatment, whereas after cimetidine administration this parameter decreased in the heart and in the liver of rats regardless of the character of inflammation.