Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.
Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.
复制标题
1,2-二甲基肼诱导的结直肠癌模型大鼠中 5-氟尿嘧啶的药代动力学和增加的肝二氢嘧啶脱氢酶活性水平。
DOI：
10.1007/s13318-012-0114-9
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Takada K.
中科院分区：
文献类型：
--
作者：
Kobuchi S;Ito Y;Okada K;Imoto K;Takada K.
为了研究结直肠癌（CRC）中肝脏二氢嘧啶脱氢酶（DPD）的活性，这对于创建患者特异性给药方案至关重要，我们在1，2-二甲基肼诱导的CRC模型大鼠（CRC大鼠）中进行了5-FU药代动力学研究。大鼠接受5-FU静脉（IV）推注后，CRC大鼠的血浆浓度-时间曲线下面积（AUC）和消除半衰期（t1/2）（分别为10.02 ± 0.37 μg h mL−1，0.30 ± 0.02 h）显著低于对照组大鼠（分别为13.46 ± 1.20 μg h mL−1，0.52 ± 0.05 h），而CRC大鼠的总血浆清除率（CLtot）（2.01 ± 0.07 L h− 1 kg −1）与对照大鼠（1.54 ± 0.14 L h− 1 kg −1）相比显著增加。相反，肝脏首过效应的回避率比对照大鼠低约20%。值得关注的是，肝DPD活性水平和血浆中的二氢尿嘧啶-尿嘧啶比率（UH 2/Ura比率）在CRC大鼠中显著增加，其可作为评价肝DPD活性水平的潜在生物标志物。这些结果表明，CRC大鼠肝脏利用度的降低是由于DPD活性增加引起的内在清除率增加，导致5-FU IV推注后AUC和t1/2降低，CL totat增加。沿着对CRC患者的适当给药方案，需要肝DPD活性监测系统，例如测定血浆中的UH 2/Ura比率。
To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine–induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration–time curve (AUC) and elimination half-life (t1/2) in CRC rats (10.02 ± 0.37 μg h mL−1, 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL−1, 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CLtot) in CRC rats (2.01 ± 0.07 L h−1kg−1) was significantly increased compared with that in control rats (1.54 ± 0.14 L h−1kg−1). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC andt1/2and an increase in CLtotafter 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.