TY - JOUR T1 - Correlation between In Vivo and In Vitro Hepatic Uptake of Metabolic Inhibitors of Cytochrome P-450 in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1225 LP - 1231 VL - 27 IS - 11 AU - Katsuhiro Yamano AU - Koujirou Yamamoto AU - Hajime Kotaki AU - Sayuri Takedomi AU - Hirotami Matsuo AU - Yasufumi Sawada AU - Tatsuji Iga Y1 - 1999/11/01 UR - http://dmd.aspetjournals.org/content/27/11/1225.abstract N2 - 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 (KBf) 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 KBf values of all nine drugs with a slope of 1. This finding suggested the possibility of predicting drug concentrations in the liver (CH) from C/M ratios, the blood concentrations of drugs (CB) and unbound fraction in blood (fB), which was expressed by CH = (C/M) · CB · fB. It may be possible to predict the drug concentrations in human liver from KBf values estimated with isolated human hepatocytes and concentrations in the blood in a similar manner as in rats. The American Society for Pharmacology and Experimental Therapeutics ER -