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Disposition of a CYP2C9 phenotyping agent losartan is not influenced by the 3435C>T variation in the drug transporter gene ABCB1 in human
Author(s) -
Babaoglu Melih O.,
Yasar Umit,
Bozkurt Atila
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1192-a
Losartan is oxidized to E3174 mainly by CYP2C9. Losartan/E3174 ratio in the eight‐hour urine can be used as an in vivo marker for the assessment of CYP2C9 activity in human. Both losartan and E3174 have also been reported to be substrates for the genetically polymorphic drug efflux transporter ABCB1, in vitro . In order to evaluate a possible confounder effect of ABCB1 variations on losartan oxidation, we investigated if losartan disposition was influenced by the 3435C>T polymorphism in healthy individuals. Subjects with the CYP2C9∗1∗1 genotype were examined for ABCB1 genotypes and CYP2C9 metabolic activity by using a single oral dose (25 mg) losartan. Within CC (n=13), CT (n=29) and TT (n=16) genotype groups for ABCB1, the urinary levels (μM; mean, SD) of either losartan (1.76, 0.87; 1.68, 0.84 and 1.80, 0.85, respectively, P=0.70) or E3174 (2.97, 2.49; 2.53, 2.09; 3.18, 2.75, respectively, P=0.65) were not significantly different from each other. Likewise, losartan/E3174 ratios (mean, SD) were similar among three ABCB1 genotype groups CC (0.91, 0.63), CT (0.99, 0.83) and TT (0.92, 0.69) (p=0.92). These results suggest that ABCB1 3435C>T polymorphism does not interfere with losartan disposition and that this polymorphism would not influence the use of the eight‐hour urinary losartan/E3174 ratio as a marker of CYP2C9 activity in vivo in human. (Supported by TUBITAK‐SBAG COST B25‐105S027 and UY/TUBA‐GEBIP/2005‐17)