Effects of liver fibrosis on verapamil pharmacokinetics in rats

1. Liver fibrosis is the compensatory state of cirrhosis. In the long asymptomatic period, it is imperative to select a proper dosing regimen for drugs that are applicable to hepatic fibrosis owing to altered pharmacokinetics and bioavailability. The present study was designed to observe the changes in verapamil pharmacokinetics in rats with early liver fibrosis with respect to alterations in cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). 2. A rat liver fibrosis model was successfully established using several inducers, including a high-fat diet, alcohol and carbon tetrachloride. After rats received a single intravenous or oral dose of verapamil (5 mg/kg), the plasma concentrations of verapamil were determined at scheduled time-points using HPLC. The activity of hepatic and small intestinal microsomal erythromycin N-demethylase (a marker for CYP3A) and the expression of small intestinal cyp3a and multidrug resistance (mdr) mRNA were compared between normal rats and rats with liver fibrosis. 3. The results showed that when verapamil was administered intravenously, the area under the curve (AUC), elimination half-life and mean residence time (MRT) increased significantly, whereas clearance (Cl) decreased, in rats with liver fibrosis compared with normal rats. After oral administration of verapamil, the AUC, T-1/2(K10) and maximum concentration (C-max) increased, Cl decreased and the absorption half-life ( T, and time to peak concentration (T-max) were unchanged compared with normal rats. The oral bioavailability of verapamil was 32.9% in normal rats and 34.4% in rats with liver fibrosis. Furthermore, decreased CYP3A activity in the liver was accompanied by upregulated cyp3a9/18 and unchanged mdr mRNA in the small intestine compared with normal rats. Expression of cyp3a9/18 and mdr mRNA in the intestine was significantly inhibited by verapamil. 4. The results suggest that the lowered Cl and increased AUC of verapamil after intravenous and oral administration in rats with liver fibrosis were due to downregulation of CYP3A in the liver. The absorption rate of verapamil in rats with liver fibrosis was unchanged because mdr was unchanged and cyp3a was inhibited in the intestine by verapamil itself. There was no notable difference in oral bioavailability between normal rats and rats with liver fibrosis.