Correlation between in vivo and in vitro hepatic uptake of metabolic inhibitors of cytochrome P-450 in rats

To predict the degree of accumulation of hepatic metabolic inhibitors in th e liver from the in vitro data, we investigated the relationship between ce ll/medium concentration ratios (C/M ratios) in isolated rat hepatocytes and liver/blood unbound concentration (K-Bf) after i.v. administration of vari ous metabolic inhibitors such as itraconazole, ketoconazole, verapamil, dil tiazem, enoxacin, ciprofloxacin, clarithromycin, cimetidine, and nizatidine . The C/M ratios of itraconazole were similar to 6000 and 200 at the concen trations of 0.1 and 10 mu g/ml, respectively, and the uptake of ketoconazol e and verapamil into the hepatocytes also showed a concentration dependence , although the degree was smaller than that of itracon-azole. The uptake of diltiazem, enoxacin, ciprofloxacin, and clarithromycin into the hepatocyte s showed linear profiles on concentration dependence. There was an excellen t correlation between C/M ratios and K-Bf values of all nine drugs with a s lope of 1. This finding suggested the possibility of predicting drug concen trations in the liver (C-H) from C/M ratios, the blood concentrations of dr ugs (CB) 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 a nd concentrations in the blood in a similar manner as in rats.