Abstract

To predict the degree of accumulation of hepatic metabolic inhibitors in the liver from the in vitro data, we investigated the relationship between cell/medium concentration ratios (C/M ratios) in isolated rat hepatocytes and liver/blood unbound concentration (K_Bf) after i.v. administration of various metabolic inhibitors such as itraconazole, ketoconazole, verapamil, diltiazem, enoxacin, ciprofloxacin, clarithromycin, cimetidine, and nizatidine. The C/M ratios of itraconazole were ∼6000 and 200 at the concentrations of 0.1 and 10 μg/ml, respectively, and the uptake of ketoconazole and verapamil into the hepatocytes also showed a concentration dependence, although the degree was smaller than that of itraconazole. The uptake of diltiazem, enoxacin, ciprofloxacin, and clarithromycin into the hepatocytes showed linear profiles on concentration dependence. There was an excellent correlation between C/M ratios and K_Bf values of all nine drugs with a slope of 1. This finding suggested the possibility of predicting drug concentrations in the liver (C_H) from C/M ratios, the blood concentrations of drugs (C_B) and unbound fraction in blood (f_B), which was expressed by C_H = (C/M) · C_B · f_B. It may be possible to predict the drug concentrations in human liver from K_Bf values estimated with isolated human hepatocytes and concentrations in the blood in a similar manner as in rats.