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Merck Frosst Centre for Therapeutic Research
As domestic animals such as cat, horse, and dog increasingly become
the clinical targets for drug discovery programs, the need to
understand how these animals metabolize xenobiotics becomes more
important. In the present study, substrates and inhibitors that were
reported to be selective for particular P450 isozymes were used as
probes to study in vitro metabolism in horse, dog, cat, and
human liver microsomes. Seven selective catalytic activity markers for
cytochrome P450-mediated reactions were measured: phenacetin
O-deethylase (P4501A1/2), coumarin 7-hydroxylase (P4502A6), tolbutamide hydroxylase (P4502C8/9), S-mephenytoin
4
-hydroxylase (P4502C19), dextromethorphan O-demethylase
(P4502D6), chlorzoxazone 6-hydroxylase (P4502E1), and testosterone
6
-hydroxylase (P4503A4). Metabolic activity was found in every
species with each substrate. Under the conditions of this study, it was
observed that no one species was more active for any given substrate.
However, rather large interspecies differences were observed. There was
no marked sex difference in the way the various species metabolized the different substrates. The effect of selective P450 inhibitors on the
various activities was tested with furafylline (P4501A2), mouse
monoclonal antibody inhibitory to CYP2A6, sulfaphenazole (P4502C9),
tranylcypromine (P4502C19), quinidine (P4502D6), diethyldithiocarbamate (P4502E1), and troleandomycin (P4503A4). In most cases, these inhibitors were effective to varying degrees against the activity seen
in horse, dog, and cat liver microsomes. However, even at high
concentrations, furafylline did not inhibit phenacetin
O-deethylase activity in cat and troleandomycin did not
affect testosterone 6-hydroxylase activity in horse. Sulfaphenazole
was not tested in dog and cat because of the low tolbutamide
hydroxylase activity. Overall, these results show that there are also
large interspecies differences in the way the selective P450 inhibitors
affect the in vitro metabolism of the various substrates in
horse, dog, and cat liver microsomes.
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