Inhibitory effect of 5-fluorouracil on cytochrome P4502C9 activity in cancer patients
Inhibitory effect of 5-fluorouracil on cytochrome P4502C9 activity in cancer patients
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DOI：
10.1111/j.1742-7843.2006.pto_304.x
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发表时间：
2006-02-01
影响因子：
3.1
通讯作者：
Yasar, U
中科院分区：
文献类型：
--
作者：
Gunes, A;Coskun, U;Yasar, U
已报告5-氟尿嘧啶与细胞色素P450 2C 9（CYP 2C 9）底物、S-华法林和苯妥英之间的药物相互作用。本研究旨在确定5-氟尿嘧啶对接受5-氟尿嘧啶治疗的结直肠癌患者（n=17）细胞色素P450 2C 9（CYP 2C 9）活性的影响。使用氯沙坦作为评估CYP 2C 9活性的标志物。在尿液中测定了氯沙坦及其CYP 2C 9依赖性代谢产物E-3174。比较5-FU治疗前后尿氯沙坦/E-3174比值。进行基因分型以检测CYP 2C 9 *2和CYP 2C 9 *3。在5-氟尿嘧啶第一个周期结束时，氯沙坦/E-3174比值比治疗前值增加了28.0%（P=0.15）。在5名患者中，在3个5-氟尿嘧啶周期后进行表型分析，代谢率显著增加了5.3倍（P=0.03）。结果表明，在大多数患者中，5-氟尿嘧啶抑制CYP 2C 9活性。当总给药剂量增加时，这种抑制作用更加明显。这一发现可能有助于解释5-氟尿嘧啶和CYP 2C 9底物之间的相互作用机制。
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.