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首页> 外文期刊>The Journal of toxicological sciences >Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans--toxicological implications.
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Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans--toxicological implications.

机译：卡培他滨在大鼠，小鼠，猴子和人类中体外代谢转化为5-FU的比较-毒理学意义。

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Capecitabine is an oral anticancer prodrug which is converted to 5-fluorouracil (5-FU) via 3 enzymatic steps, these being 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU by carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TP), respectively. Because rats, mice and monkeys are used for preclinical safety studies, we investigated the in vitro conversion from capecitabine to 5-FU by hepatic and intestinal mucosal microsomes and cytosols, to compare their metabolic activity to that of humans. Capecitabine was hydrolyzed to 5'-DFCR in hepatic and intestinal mucosal microsomes in these animal species. In humans and monkeys, CL(int) (V(max)/K(m)) for the hydrolysis of capecitabine in intestine (expressed as microl/min/g tissue) was much lower than that in hepatic microsomes but, in rats and mice, CL(int) was higher in intestine than in liver. In humans and monkeys, similar K(m) values and inhibition patterns by tetrahydrouridine (THU) a CDA inhibitor, were observed in CDA activity of hepatic and intestinal cytosols. However, rats showed very low CDA activity and mice showed non-Michaelis-Menten kinetics and a different inhibition pattern by THU. K(m) values for TP activity were almost similar in rats, mice, monkeys and humans. In conclusion, it was confirmed that monkeys are a suitable animal model for the safety assessment of capecitabine in terms of metabolic enzymes and it was suggested that higher toxic incidences in mouse small intestine were related to high hydrolytic activity of capecitabine in the small intestine.
机译：卡培他滨是一种口服抗癌前药，可通过3个酶促步骤转化为5-氟尿嘧啶（5-FU），分别是5'-脱氧-5-氟胞苷（5'-DFCR），5'-脱氧-5-氟尿苷（5 '-DFUR），最后分别由羧基酯酶（CES），胞苷脱氨酶（CDA）和胸苷磷酸化酶（TP）合成5-FU。因为大鼠，小鼠和猴子用于临床前安全性研究，所以我们研究了肝，肠黏膜微粒体和细胞溶质从卡培他滨向5-FU的体外转化，以比较其与人的代谢活性。在这些动物的肝脏和肠粘膜微粒体中，卡培他滨被水解为5'-DFCR。在人和猴子中，卡培他滨在肠道中的水解度（以微升/分钟/克组织表示）的CL（int）（V（max）/ K（m））远低于肝微粒体，但在大鼠和小鼠的肠内CL（int）高于肝脏。在人和猴子中，肝和肠细胞质溶胶的CDA活性观察到相似的K（m）值和CDA抑制剂四氢尿苷（THU）的抑制模式。但是，大鼠表现出非常低的CDA活性，而小鼠表现出非Michaelis-Menten动力学和不同的THU抑制模式。 TP活性的K（m）值在大鼠，小鼠，猴子和人类中几乎相似。总之，已证实猴子是用于卡培他滨安全性评估代谢酶的合适动物模型，并且表明小鼠小肠中较高的毒性发生率与卡培他滨在小肠中的高水解活性有关。

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