Table 3

Comparison of observed in vivo metabolic clearance of tolbutamide with predicted values from human liver microsomal data obtained in the absence and presence of 5 mg/ml Hsa and 0.5 mg/ml Hlc

Without Hsa and HlcWith HsaWith HlcWith Hsa and Hlc
K m,u 3-a(μM)123 (10)73 (5)88 (12)64 (5)
V max,u 3-a(pmol/mg/min)282 (9)305 (7)292 (16)327 (8)
CLint,u 3-b(μl/min/mg)2.34.23.35.1
CLint,u 3-c(ml/min/kg)2.13.83.04.6
CLh,u 3-d (predicted, ml/min/kg)0.060.110.090.14
CLmet 3-e (actual, ml/min/kg)0.15 [0.019]3-f
  • 3-a  Km,u andVmax,u were determined by fitting the mean of duplicate determinations of reaction velocity versus unbound tolbutamide concentration data (determined by duplicate incubations at each tolbutamide concentration in each of the incubation media) to the Michaelis-Menten equation. Data in the parentheses represent the standard error of fitting function for each kinetic parameter.

  • 3-b  In vitro CLint,u calculated using Vmax,u/Km,u.

  • 3-c  Predicted in vivo CLint,u.

  • 3-d  Hepatic clearance predicted using the well stirred model.

  • 3-e  In vivo CLmet of tolbutamide hydroxylation observed in human subjects (data fromGross et al., 1999).

  • 3-f  Value is mean (S.D.) of 10 individuals. See Experimental Procedures for details.