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Vol. 28, Issue 7, 807-813, July 2000
Department of Pharmaceutical Sciences (K.S.P.), Faculty of Pharmacy
and Department of Pharmacology (T.N.A., K.S.P.), Faculty of Medicine,
University of Toronto, Toronto, Ontario, Canada
Previous studies showed that the transport of enalapril occurred
homogeneously among zonal rat hepatocytes. However, the metabolism of
hepatic arterially delivered enalapril, swept into the rat liver by the
portal or hepatic venous flow (HAPV and HAHV perfusion), was
more abundant in the perivenous (PV) than the periportal (PP) region. Hence, metabolic activities toward enalapril in
9000g supernatant (S9) fractions of enriched rat PP and
PV hepatocytes were examined. Although Michaelis-Menten kinetics were
invariably observed, the metabolic activity toward enalapril (intrinsic
clearance or
Vmaxmet/Kmmet
of 0.008 ml/min/mg of S9 protein,
Vmaxmet of 21 ± 6 nmol/min/mg of
S9 protein, and Kmmet of 2612 ± 236 µM) was greater in PV than in PP
(Vmaxmet of 5.5 ± 3.1 nmol/min/mg of S9 protein and Kmmet of
1049 ± 335 µM; intrinsic clearance of 0.0052 ml/min/mg of S9
protein) hepatocytes. These metabolic intrinsic clearances were much
lower than the sinusoidal influx clearances observed from previous
transport studies, revealing metabolism as the rate-limiting step.
Substitution of the scaled-up transport and metabolic intrinsic clearances into the "well stirred", "parallel-tube", and
"dispersion" models predicted higher steady-state extraction ratios
for HAHV perfusion. By contrast, integration of the scaled-up in vitro parameters on zonal metabolism and homogeneous transport into a
"zonal-compartment" model of three zonal subcompartments (1, 2, and
3) provided an improved description of the extraction ratios during
HAPV and HAHV. Zonal factors are important for the scale-up of data in
vitro to the whole organ.
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