title: The inhibitory effects of cimetidine on elimination and distribution of propranolol in rats.
abstract: 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.
authors.affiliation: School of Pharmaceutical Science, Toho University, Chiba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shibasaki
authors.forename: M
authors.initials: M
authors.lastname: Asahina
authors.forename: Y
authors.initials: Y
authors.lastname: Kawamata
authors.forename: M
authors.initials: M
authors.lastname: Kojo
authors.forename: R
authors.initials: R
authors.lastname: Nishigaki
authors.forename: K
authors.initials: K
authors.lastname: Umemura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology*; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011433:Propranolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D001798:Blood Proteins; D002927:Cimetidine; D011433:Propranolol