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Background: Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme catalyzing the metabolism of several important drugs. CYP2C9 metabolizes a number of therapeutically important drugs, including most nonsteroidal anti-inşammatory drugs, S-warfarin, phenytoin, and losartan. CYP2C9 is also involved in the metabolism of several important psychoactive substances (tetrahydrocannabinol, şuoxetine, amitriptyline, phenytoin, etc.). It has been reported that CYP2C9 activity is modulated by endogenous substrates such as adrenaline and serotonin. The involvement of CYP2C9 in the metabolism of melatonin has also been suggested. Losartan has recently been suggested as a selective probe for CYP2C9 metabolic activity.
Objective: The aim of the study was to determine the activity of CYP2C9, using losartan as a probe drug, in relation to CYP2C9 genotype in healthy Ecuadorian subjects.
Methods: A single oral dose of 50 mg losartan was given to 194 Ecuadorian unrelated subjects. Concentrations of losartan and its carboxylic acid metabolite, E3174, were analyzed by means of high-performance liquid chromatography in urine collected for 8 h. The CYP2C9 genotypes were determined in 194 subjects using specific methods for CYP2C9*2 and CYP2C9*3.
Results: The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3 were 0.054 and 0.015, respectively. The urinary losartan/E3174 ratio was significantly higher (p=0.027) in subjects with the CYP2C9*1/*3 genotype (mean±SD, 12.4±13.8; n=6) than in subjects with the CYP2C9*1/*1 (4.9±7.0; n=167).
Conclusion: This is the first most extensive population where losartan has been used as a probe drug to evaluate the CYP2C9 activity in vivo. The urinary losartan to E3174 metabolic ratio after a 50mg losartan dose was found to be a safe and useful phenotyping assay for CYP2C9 activity in vivo. The CYP2C9*3 variant allele is a major determinant of the enzyme activity, and it decreases losartan metabolism significantly, while the CYP2C9*2 allele has less impact on enzyme function.