The In vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes.

Article Details

Citation

Zhao XJ, Ishizaki T

The In vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes.

J Pharmacol Exp Ther. 1997 Dec;283(3):1168-76.

PubMed ID
9399990 [ View in PubMed
]
Abstract

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 alpha-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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
DoxycyclineCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details
TetracyclineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details