A method for quantitatively predicting the hepatic clearance of drugs by UDP-glucuronosyltransferases (UGTs) from
in vitro data has not yet been established. We examined the relationship between
in vitro and
in vivo intrinsic clearance by rat hepatic UGTs using 10 drugs. For these 10 drugs, the
in vitro intrinsic clearance by UGTs (CL
int, in vitro) measured using alamethicin-activated rat liver microsomes was in the range 0.10–4500 ml/min/kg. Microsomal binding (f
u, mic) was determined to be in the range 0.29–0.95 and the unbound intrinsic clearance (CL
uint, in vitro) to be in the range 0.11–9600 ml/min/kg. The contribution of rat hepatic glucuronidation to drug elimination was 12.0%–76.6% and
in vivo intrinsic clearance by UGTs was 5.7–9000 ml/min/kg. To evaluate the discrepancy between the
in vitro and
in vivo values, a scaling factor was calculated (CL
int, in vivo/CL
int, in vitro); the values were found to be in the range 0.89–110. The average fold error of the scaling factor values incorporating f
u, mic was closer to unity than that without f
u, mic. The scaling factor values incorporating f
u, mic were <10 in 8/10 drugs and <2 in 6/10 drugs, indicating a small discrepancy between
in vitro and
in vivo values. Thus, using alamethicin-activated liver microsomes, incorporating f
u, mic into CL
int, in vitro, and considering the contribution of glucuronidation may enable us to quantitatively predict
in vivo hepatic glucuronidation from
in vitro data.
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