title: Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction.
abstract: The effects of renal failure on the hepatic and intestinal extraction of tacrolimus were evaluated to examine the mechanisms for the increased bioavailability of this drug in cisplatin-induced renal failure model rats. Tacrolimus extractions in the liver and intestine were evaluated by intravenous, intraportal and intraintestinal infusion. The intestinal metabolism and absorption rate were estimated by incubating the isolated intestine with drug solution and by an in situ loop method, respectively. Blood concentrations of tacrolimus following the intraintestinal infusion were significantly increased in rats with renal failure compared with those in normal rats. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine from rats with renal dysfunction. These results suggest that the hepatic metabolism of tacrolimus is impaired in rats with renal failure, and that the accelerated absorption rate in the intestine in renal dysfunction is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Okabe
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001682:Biological Availability; D002945:Cisplatin / Q000633:toxicity; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D002945:Cisplatin; D016559:Tacrolimus