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Received for publication April 25, 2006.
Revised June 16, 2006.
Accepted for publication June 19, 2006.
Apparent intrinsic clearance (CLint,app) of the 7-ethoxycoumarin, phenacetin, propranolol, and midazolam was measured using rat and human liver microsomes, 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, albeit there was greater variability using the latter system. The CLint,app values in hepatocytes are observed to be lower than that in microsomes and this difference becomes greater for compounds with high CLint,app. This could partly be attributed to the differences in the free fraction (fu). The fu in hepatocyte incubations (fu,hep-inc) was influenced not only by the free fraction of compounds in the incubation buffer (fu,buffer) but also by the rate constants of uptake (kup) and metabolism (kmet). This report provides a new derivation for fu,hep which can be expressed as: fu,hep-inc = [kup / (kmet + kup)] / [1 + (Chep / Cbuffer) x (Vhep / Vbuffer)], where the Chep, Cbuffer, Vhep, and Vbuffer represent the concentrations of a compound in hepatocytes and buffer, and volumes of hepatocytes and buffer, respectively. For midazolam, the fu,hep-inc was calculated and the maximum metabolism rate in hepatocytes was shown to be limited by the uptake rate.
Key words:
drug clearance, in vitro-in vivo prediction, isolated hepatocytes, liver microsomes
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