title: Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat.
abstract: The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.
authors.affiliation: Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, DF, México.
authors.forename: Liliana
authors.initials: L
authors.lastname: Rivera-Espinosa
authors.forename: Pablo
authors.initials: P
authors.lastname: Muriel
authors.forename: Mónica
authors.initials: M
authors.lastname: Ordaz Gallo
authors.forename: José
authors.initials: J
authors.lastname: Pérez-Urizar
authors.forename: Antonio
authors.initials: A
authors.lastname: Palma-Aguirre
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernández
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001652:Bile Ducts / Q000601:surgery; D001682:Biological Availability; D004195:Disease Models, Animal; D020910:Ketorolac / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008026:Ligation; D008099:Liver / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005723:gamma-Glutamyltransferase; D020910:Ketorolac