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Vol. 297, Issue 1, 326-337, April 2001
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine, and the Division of Clinical
Pharmacology, New England Medical Center, Boston, Massachusetts
The relative activity factor (RAF) approach is being increasingly used
in the quantitative phenotyping of multienzyme drug biotransformations.
Using lymphoblast-expressed cytochromes P450 (CYPs) and the tricyclic
antidepressant amitriptyline as a model substrate, we have tested the
hypothesis that the human liver microsomal rates of a biotransformation
mediated by multiple CYP isoforms can be mathematically reconstructed
from the rates of the biotransformation catalyzed by individual
recombinant CYPs using the RAF approach, and that the RAF approach can
be used for the in vitro-in vivo scaling of pharmacokinetic clearance from in vitro intrinsic clearance measurements in heterologous expression systems. In addition, we have compared the results of two
widely used methods of quantitative reaction phenotyping, namely,
chemical inhibition studies and the prediction of relative contributions of individual CYP isoforms using the RAF approach. For
the pathways of N-demethylation (mediated by CYPs 1A2,
2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and E-10 hydroxylation (mediated by
CYPs 2B6, 2D6, and 3A4), the model-predicted biotransformation rates in
microsomes from a panel of 12 human livers determined from enzyme
kinetic parameters of the recombinant CYPs were similar to, and
correlated with the observed rates. The model-predicted clearance via
N-demethylation was 53% lower than the previously reported in vivo pharmacokinetic estimates. Model-predicted relative contributions of individual CYP isoforms to the net biotransformation rate were similar to, and correlated with the fractional decrement in
human liver microsomal reaction rates by chemical inhibitors of the
respective CYPs, provided the chemical inhibitors used were specific to
their target CYP isoforms.
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