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Vol. 29, Issue 7, 1051-1056, July 2001
Division of Clinical Pharmacology, Department of Medical Laboratory
Sciences and Technology, Karolinska Institutet, Huddinge University
Hospital, Stockholm, Sweden (Ü.Y., G.T., M.-L.D., E.E.); and
Division of Molecular Toxicology, National Institute of Environmental
Medicine, Karolinska Institutet, Stockholm, Sweden (M.H., M.O.,
M.I.-S.)
Losartan, an angiotensin II receptor antagonist, is oxidized by
hepatic cytochromes P450 to an active carboxylic acid metabolite, E-3174. The aim of the present investigation was to study the contribution of CYP2C9 and CYP3A4 in losartan oxidation in vitro and to
evaluate the role of CYP2C9 polymorphism. Kinetic
properties of different genetic CYP2C9 variants were compared both in a
yeast expression system and in 25 different samples of human liver
microsomes where all known genotypes of CYP2C9 were
represented. Microsomes were incubated with losartan (0.05-50 µM),
and the formation of E-3174 was analyzed by high-performance liquid
chromatography to estimate Vmax,
Km, and intrinsic clearance for all
individual samples. Sulfaphenazole, a CYP2C9 inhibitor, blocked the
formation of E-3174 at low losartan concentrations (<1 µM), whereas
the inhibitory effect of triacetyloleandomycin, a CYP3A4 inhibitor, was
significant only at high concentrations of losartan (>25 µM). In
comparison to the CYP2C9.1 variant, oxidation of losartan was significantly reduced in yeast expressing the rare CYP2C9.2 or CYP2C9.3
variants. Moreover, the rate of losartan oxidation was lower in liver
microsomes from individuals hetero- or homozygous for the
CYP2C9*3 allele, or homozygous for the
CYP2C9*2 allele. The difference between the common and
rare CYP2C9 variants was mainly explained by a lower
Vmax, both in yeast and human liver microsomes. In summary, these in vitro results indicate that CYP2C9 is
the major human P450 isoenzyme responsible for losartan oxidation and
that the CYP2C9 genotype contributes to interindividual
differences in losartan oxidation and activation.
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