摘要：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 (β) 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 cnanged. The hepatic blood flow rate (Qh) and the product of the plasma unbound fraction and the hepatic intrinsic clearance (fp×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 (0.1-1.0μg/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.
