TABLE 1

Parameters describing hepatically derived enalaprilat disposition in human SCH

Human SCH were incubated with 5 µM enalapril with and without MK-571 (25 µM) for 60 minutes. Enalapril and enalaprilat concentrations in the post-efflux medium, and in hepatocytes pre- and post-efflux, were quantified as described in Materials and Methods. Data are presented as the mean ± S.D.; n = 3 independent hepatocyte preparations performed in triplicate.

Kinetic ParametersEnalapril (5 µM) ControlEnalapril (5 µM) + MK-571 (25 µM)
Pre-efflux
 Pre-efflux enalaprilat cellular concentration (pmol/µl)
  Liver 125.5 ± 2.56.9 ± 0.6
  Liver 25.5 ± 0.33.0 ± 0.1
  Liver 36.5 ± 0.72.0 ± 0.2
  Mean12.5 ± 11.34.0 ± 2.6
Post-efflux
 Post-efflux enalaprilat cellular concentration (pmol/µl)
  Liver 120.4 ± 1.75.2 ± 0.2
  Liver 25.2 ± 0.63.1 ± 0.2
  Liver 36.7 ± 0.82.4 ± 0.1
  Mean10.8 ± 8.43.6 ± 1.5
 Mass enalaprilat excreted into efflux buffer (XEfflux Buffer 0→30, pmol)
  Liver 116.9 ± 1.50.8 ± 1.3
  Liver 22.3a0.4 ± 0.7
  Liver 37.5 ± 0.61.3 ± 0.5
  Mean8.9 ± 7.40.8 ± 0.4
Cellular enalaprilat exposure (AUCCell 0→30, pmol⋅min/µl)
 Liver 1684 ± 16.9180 ± 3.2
 Liver 2160 ± 13.691.3 ± 3.4
 Liver 3199 ± 16.265.4 ± 4.3
 Mean348 ± 293112 ± 60.4
Basolateral enalaprilat clearance (CLint, basolateral, µl/min)
 Liver 10.024 ± 0.0010.004 ± 0.004
 Liver 20.014a0.004 ± 0.007
 Liver 30.037 ± 0.0020.019 ± 0.008
 Mean0.026 ± 0.0120.009 ± 0.009 *

  • ↵a Value imputed due to analytical error as the difference in enalaprilat intracellular concentration pre- versus post-efflux, assuming a cellular volume of 7.69 µl/mg protein.

  • ↵* P < 0.05 vehicle control versus MK-571.