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Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes

Drug Metabolism and Pharmacokinetics, Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

Apparent intrinsic clearance (CL_int,app) of 7-ethoxycoumarin, phenacetin, propranolol, and midazolam was measured using rat and human liver microsomes and freshly isolated and cryopreserved hepatocytes to determine factors responsible for differences in rates of metabolism in these systems. The cryopreserved and freshly isolated hepatocytes generally provided similar results, although there was greater variability using the latter system. The CL_int,app values in hepatocytes are observed to be lower than that in microsomes, and this difference becomes greater for compounds with high CL_int,app. This could partly be attributed to the differences in the free fraction (f_u). The f_u in hepatocyte incubations (f_u,hep-inc) was influenced not only by the free fraction of compounds in the incubation buffer (f_u,buffer) but also by the rate constants of uptake (k_up) and metabolism (k_met). This report provides a new derivation for f_u,hep-inc, which can be expressed as f_u,hep-inc = [k_up/(k_met + k_up)]/[1 + (C_hep/C_buffer) x (V_hep/V_buffer)], where the C_hep, C_buffer, V_hep, and V_buffer represent the concentrations of a compound in hepatocytes and buffer and volumes of hepatocytes and buffer, respectively. For midazolam, the f_u,hep-inc was calculated, and the maximum metabolism rate in hepatocytes was shown to be limited by the uptake rate.

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