Effects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus in rats

Background: To investigate the effects 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 effects 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: After 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. The 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. The area under the blood concentration-time curve after intraloop administration of tacrolimus with double-diluted bile or with saline was significantly lesser than that with undiluted bile. Significant 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: The decrease in the hepatic intrinsic clearance of tacrolimus in rats with bile duct ligation suggests that the bile duct stricture might contribute to the clinically observed interand intra-patient pharmacokinetic variability. The 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.