Hepatic extraction of tacrolimus in rats with experimental liver diseases

Tacrolimus, an immunosuppressive agent, is metabolized mainly in the liver and has shown large intra- and interindividual pharmacokinetic variability. We investigated the effect of liver dysfunctions on the pharmacokinetics of tacrolimus in rats with experimental liver diseases. Experimental hepatic failure was induced by CCl₄-treatment or bile duct ligation. Tacrolimus (1 or 0.3 mg/kg) was administered intravenously or intraportally to the rats (n=5-6 per group), and blood samples were collected over a 240-min period. The tacrolimus concentrations in the blood were then measured by a high-performance liquid chromatography-enzyme immunoassay. In the normal rats, the hepatic extraction ratio of tacrolimus (E(H)) was dose- independent, ranging from 0.556-0.598 at 0.3 and 1.0 mg/kg doses. The E(H) were dose-dependent in the CCl₄-treated rats and in the bile duet-ligated rats: the E(H) at 1.0 mg/kg dose were 0.158-0.170 and those at 0.3 mg/kg dose were 0.329-0.394. The intermediate E(H) of tacrolimus suggested that the clearance of tacrolimus depends not only on hepatic intrinsic clearance but also on hepatic blood flow. The present pharmacokinetic study also suggested that the decrease of E(H) and the dose-dependence of E(H) contribute to the elevation of blood tacrolimus concentrations and to the large variability in the pharmacokinetics of tacrolimus after oral administration in hepatic dysfunctions.