The In vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes.
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.
Zhao
X J
XJ
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Ishizaki
T
T
D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D011803:Quinine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000962:Antimalarials; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine