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Vol. 283, Issue 3, 1168-1176, 1997
Department of Clinical Pharmacology, Research Institute,
International Medical Center of Japan, Tokyo, Japan
The major metabolic pathway of quinine in the human has been
shown to be 3-hydroxylation mediated mainly by human cytochrome P450
(CYP) 3A4. In this extended in vitro study, quinine
3-hydroxylation was further investigated using microsomes from mouse,
rat, dog and human livers and was compared among them in terms of the
in vitro enzyme-kinetic parameters and quinine-drug
interaction screenings. In all species, 3-hydroxyquinine was the
principal metabolite of quinine. There was intra- and interspecies
variability among all the kinetic parameters, and dogs exhibited a
closer resemblance to humans in terms of the mean kinetic data.
Ketoconazole and troleandomycin inhibited the 3-hydroxylation of
quinine in all species. Both 
-naphthoflavone and diazepam showed an
interspecies difference in quinine 3-hydroxylation: a trend toward an
activation in dog and human, and a significant inhibition in mouse and
rat, liver microsomes. Antisera raised against rat CYP3A2 strongly inhibited quinine 3-hydroxylation by about 96, 84 and 92% with mouse,
rat and dog liver microsomes, respectively, but neither anti-rat 2C11
and 2E1 antisera did so with rat liver microsomes. Primaquine,
doxycycline and tetracycline substantially inhibited the formation of
3-hydroxyquinine in rat, dog and human species, but proguanil had no
such effect in any species. Chloroquine inhibited quinine
3-hydroxylation with rat and dog liver microsomes but not with human
liver microsomes. There was a significant correlation (r = 0.986, P < .001) between the CYP3A contents
and the formation rates of 3-hydroxyquinine in eight human liver
microsomal samples. It is concluded that 3-hydroxyquinine is a main
metabolite of quinine and that CYP3A/Cyp3a is a principal isoform
involved in this metabolic pathway in the respective (rat, dog and
human/mouse) species tested. The dog and possibly the rat may be
qualitatively and quantitatively suitable animal models for exploring
the quinine 3-hydroxylase activity and for screening quinine-drug
interactions in vitro, at certain inconsistency with the
human liver microsomal data.
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