Interactive Medicinal Chemistry ISSN 2053-7107 Research Open Access Effects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus in rats Shinji Kobuchi 1* , Keizo Fukushima 2 , Yuta Maeda 1 , Takatoshi Kokuhu 3 , Hidetaka Ushigome 4 , Norio Yoshimura 4 , Nobuyuki Sugioka 2 and Kanji Takada 1 *Correspondence: ky05122@poppy.kyoto-phu.ac.jp 1 Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. 2 Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan. 3 Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kamigyou-ku Kyoto, Japan. 4 Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kamigyou-ku Kyoto, Japan. Abstract Background: To investigate the efects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus, the pharmacokinetics of tacrolimus in rats with bile duct ligation were evaluated and the efects of the amount of intestinal bile on intestinal tacrolimus absorption were determined. Methods: In vivo pharmacokinetic studies and in vitro metabolic studies in rats with bile duct ligation were performed. In addition, an in situ absorption study was performed. Results: Ater an intravenous bolus injection of tacrolimus, the area under the blood concentration-time curve in rats with bile duct ligation was approximately 1.9-fold greater than that in control rats. he total clearance and steady-state volume of distribution decreased in the rats with bile duct ligation by 44.1% and 40.4%, respectively. Moreover, the production ratios of demethyl-tacrolimus and hydroxy-tacrolimus in the hepatic microsomes of rats with bile duct ligation were 59–62% and 21–43%, respectively, lower than the corresponding ratios in control rats. he area under t he blood concentration-time curve ater intraloop administration of tacrolimus with double-diluted bile or with saline was signiicantly lesser than that with undiluted bile. Signiicant positive linear correlations were observed between the amount of intestinal bile and the area under the blood concentration-time curve of tacrolimus ( r=0.999, p<0.05). Conclusions: he decrease in t he hepatic intrinsic clearance of tacrolimus in rats with bile duct ligation suggests that the bile duct stricture might contribute to the clinically observed inter- and intra-patient pharmacokinetic variability. he amount of bile in the intestine is an important factor that should be considered during tacrolimus treatment. When the route of administration of tacrolimus is changed from injection to an oral one or during long-term oral administration of tacrolimus in patients with bile duct stricture, the decrease in absorption should be taken into account, and the dose should be adjusted accordingly. Taken together, the data indicate that personalized therapy is required for patients with bile duct stricture, and it is necessary to carefully evaluate therapeutic drug monitoring data for tacrolimus. Keywords: Pharmacokinetics, bile ducts, tacrolimus, therapeutic drug monitoring © 2013 Kobuchi et al; licensee Herbert Publications Ltd. his is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). his permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Tacrolimus (TAC), an immunosuppressive agent (molecular weight of the non-hydrate form, 806), inhibits the signal transduction pathway involved in the activation of T-lymphocytes [1,2]. TAC is used for preventing or treating graft rejection after organ transplantation [3], and is superior to cyclosporine (CyA) in improving survival (patient and graft) and preventing acute rejection in living donor liver transplantation patients [4]. TAC is the drug of choice for living donor liver transplant recipients in our university hospital, Kyoto Prefectural University of Medicine. The pharmacokinetics (PK) of TAC are characterized by a marked and unexplained variability, particularly in the early period after transplantation [5,6]. TAC is highly lipophilic and insoluble in water, and is a substrate for the drug efflux pump, P-glycoprotein (Pgp), and the metabolizing enzyme, cytochrome P450 (CYP) 3A. These physicochemical properties of TAC contribute to the large variation in oral absorption and extensive metabolic clearance from the body. In addition, TAC has a narrow therapeutic window and thus therapeutic drug monitoring (TDM) is essential for maintaining efficacy [7,8] and minimizing the toxicity of TAC [9,10]. Liver transplantation is a widely accepted treatment for patients with end-stage hepatic disease. Despite improvements in organ preservation technology, surgical technique, and immunosuppressive strategies, postoperative biliary stricture after liver transplantation is still a significant cause of morbidity and mortality [11]. Bile duct anastomotic stricture is a common problem after orthotopic liver transplantation, with an incidence of 15–20% [12]. Accumulation of bile acids in liver tissue because of biliary obstruction leads to production of free radicals, activation of hepatic stellate cells, and liver fibrosis [13-15]. In addition, cholestasis caused by bile duct ligation