Inhibitory effect of 5-fluorouracil on cytochrome P450 2C9 activity in cancer patients.
Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (n=17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (P=0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (P=0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.
Gunes
Arzu
A
Department of Pharmacology, Gazi University, Medical Faculty, Ankara, Turkey.
Coskun
Ugur
U
Boruban
Cem
C
Gunel
Nazan
N
Babaoglu
Melih O
MO
Sencan
Orhan
O
Bozkurt
Atila
A
Rane
Anders
A
Hassan
Moustapha
M
Zengil
Hakan
H
Yasar
Umit
U
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000652:urine; D019808:Losartan / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D013777:Tetrazoles / Q000652:urine
D000964:Antimetabolites, Antineoplastic; D007093:Imidazoles; D013777:Tetrazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C066026:losartan carboxylic acid; D019808:Losartan; D005472:Fluorouracil