CYP2C9 genetic variants and losartan oxidation in a Turkish population.
OBJECTIVE
Cytochrome P(450) 2C9 (CYP2C9) is a polymorphic enzyme catalysing the metabolism of several important drugs. Losartan has recently been suggested as a selective probe for CYP2C9 metabolic activity. 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 Turkish subjects.


METHODS
A single oral dose of 25 mg losartan was given to 85 Turkish unrelated subjects. Concentrations of losartan and its carboxylic acid metabolite, E3174, were analysed by means of high-performance liquid chromatography in urine collected for 8 h. The CYP2C9 genotypes were determined in 85 subjects using polymerase chain reaction-based endonuclease digestion methods specific for CYP2C9*2 and *3. Losartan oxidation was also studied in vitro, using human CYP2C8 and CYP2C9 enzymes expressed in yeast.


RESULTS
The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3 were 0.100 and 0.088, respectively. The urinary losartan/E3174 ratio was significantly higher in subjects with CYP2C9*1/*3 genotype (median 2.35, n=12) than in subjects with CYP2C9*1/*1 (0.71, n=58) and *1/*2 (0.85, n=10) genotypes ( P<0.05). In contrast to CYP2C9, no E3174 was formed by CYP2C8 in vitro.


CONCLUSIONS
The urinary losartan to E3174 metabolic ratio after a 25-mg losartan dose was found to be a safe and useful phenotyping assay for CYP2C9 activity in vivo. CYP2C9*3 variant allele is a major determinant of the enzyme activity, and it decreases losartan metabolism significantly, while CYP2C9*2 allele has less impact on enzyme function.
Babaoglu
Melih O
MO
Department of Pharmacology, Hacettepe University Faculty of Medicine, 06100 Sihhiye, Ankara, Turkey. babaoglu@hacettepe.edu.tr
Yasar
Umit
U
Sandberg
Mia
M
Eliasson
Erik
E
Dahl
Marja-Liisa
ML
Kayaalp
S Oguz
SO
Bozkurt
Atila
A
D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000378:metabolism* / Q000652:urine; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D019808:Losartan / Q000009:adverse effects / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D014421:Turkey
D000959:Antihypertensive Agents; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan