The inhibitory effects of cimetidine on elimination and distribution of propranolol in rats.

We studied the effects of cimetidine on the pharmacokinetics, blood and tissue distribution and plasma protein binding of propranolol in rats. The plasma disappearance of propranolol after a 10 mg/kg intravenous injection and oral administration were fitted to a two compartment open model. In the cimetidine treated rats, the area under concentration curve after an intravenous injection (AUCiv) was increased by 64% and the plasma total body clearance (Cltot) and the rate constant at the terminal phase (beta) were decreased by 38% and 33% of those of the non-treated rats, respectively. The area under the concentration curve after oral administration (AUCpo) was increased by 62% and the plasma oral clearance (Clpo) was decreased by 39% by cimetidine treatment, whereas the bioavailability (F) was not changed. The hepatic blood flow rate (Qh) and the product of the plasma unbound fraction and the hepatic intrinsic clearance (fp x Clint,h) calculated from Cltot and Clpo were decreased by 30% and 39%, respectively. The blood-to-plasma concentration ratio (Rb) and the tissue-to-plasma concentration ratio (Kp) of propranolol were not affected by cimetidine treatment, while the binding constant (Kb) in plasma was decreased by 45%. The plasma unbound fractions (fp) of propranolol were increased by 25-70% in the in vivo plasma concentration range (0.1-1.0 microgram/ml) resulting in the decrease of tissue-to-plasma unbound concentration ratio (Kp,u) in lung, heart, spleen, brain and muscle. Cimetidine was shown to have the inhibitory effects on elimination and distribution of propranolol in rats.