RT Journal Article
SR Electronic
T1 Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1600
OP 1605
DO 10.1124/dmd.106.010793
VO 34
IS 9
A1 Chuang Lu
A1 Ping Li
A1 Richard Gallegos
A1 Vinita Uttamsingh
A1 Cindy Q. Xia
A1 Gerald T. Miwa
A1 Suresh K. Balani
A1 Liang-Shang Gan
YR 2006
UL http://dmd.aspetjournals.org/content/34/9/1600.abstract
AB Apparent intrinsic clearance (CLint,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 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-inc, which can be expressed as fu,hep-inc = [kup/(kmet + kup)]/[1 + (Chep/Cbuffer) × (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. The American Society for Pharmacology and Experimental Therapeutics