Journal of JPP 2002, 54: 65–70 # 2002 The Authors Received April 27, 2001 Accepted August 16, 2001 ISSN 0022-3573 Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction Hiromi Okabe, Ikuko Yano, Yukiya Hashimoto, Hideyuki Saito and Ken-ichi Inui 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 signicantly 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 signicantly 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. Introduction Tacrolimus is a macrolide lactone with potent immunosuppressive properties that is used clinically for the prophylaxis of organ rejection after liver, heart, small bowel and kidney transplantation. Blood tacrolimus concentrations in patients have to be kept within a narrow therapeutic range (5±20 ng mL - 1 ) because of the side eŒects of tacrolimus, such as neurotoxicity and nephrotoxicity (Venkataramanan et al 1995). Tacrolimus is rapidly absorbed after oral administration and is extensively metabolized by cytochrome P450 (CYP)3A in the liver of humans and rats (Venkataramanan et al 1995; Iwasaki et al 1998). The bioavailability of tacrolimus is low in both humans and rats (Yasuhara et al 1995; Okabe et al 2000). Moreover, we studied the metabolism of tacrolimus in the intestine and showed that the small intestine, as well as the liver, contributes signi®cantly to the ®rst-pass eŒects of tacrolimus after oral administration in rats (Hashimoto et al 1998). Although renal failure is commonly thought to aŒect only the renal elimination of drugs, it has a variety of in¯uences on drug kinetics : it may reduce non-renal elimination, in¯uence protein binding and alter the volume of distribution of some drugs (Gibson 1986). The bioavailability of some drugs is also aŒected by renal Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan Hiromi Okabe, Ikuko Yano, Hideyuki Saito, Ken-ichi Inui Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Toyama 930-0194, Japan Yukiya Hashimoto Correspondence : Ken-ichi Inui, Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606–8507, Japan. E-mail : inui!kuhp.kyoto-u.ac.jp Funding : This work was supported in part by a Grant-in- Aid for Scientic Research from the Ministry of Education, Science, Sports and Culture of Japan, a Grant-in-Aid from Japan Health Sciences Foundation, and a Grant from the Yamanouchi Foundation for Research on Metabolic Disorders. 65