卡培他滨 - CAS号 154361-50-9

物化性质

熔点：

110-121°C
密度：

1.49±0.1 g/cm3(Predicted)
闪点：

87℃
溶解度：

H2O: 可溶10mg/mL, 透明 (加热)
物理描述：

Solid
颜色/状态：

White to off-white crystalline powder
蒸汽压力：

1.12X10-12 mm Hg at 25 °C (est)
稳定性/保质期：

Capecitabine tablets reportedly are stable for at least 9 months when stored in tightly closed containers at room temperature.
解离常数：

pKa1 = 1.9 (amide)

计算性质

辛醇/水分配系数(LogP)：

0.6
重原子数：

25
可旋转键数：

7
环数：

2.0
sp3杂化的碳原子比例：

0.666
拓扑面积：

121
氢给体数：

3
氢受体数：

7

ADMET

代谢

通过胸苷酸酶代谢成氟尿嘧啶。

Metabolized by thymidine phosphorylase to fluoruracil.

来源:DrugBank

代谢

卡培他滨是一种抗肿瘤前药，被认为通过三种酶生物转化为活性5-氟尿嘧啶（5-FU）。口服给药后，卡培他滨首先被羧酸酯酶（CES）代谢为5'-脱氧-5-氟胞苷（5'-DFCR），然后5'-DFCR通过胞苷脱氨酶转化为5'-脱氧-5-氟尿苷（5'-DFUR）。5'-DFUR通过胸腺嘧啶磷酸化酶激活为5-FU。尽管药物代谢酶在人类肝脏中高活性表达，但肝脏在卡培他滨代谢中的作用尚未完全了解。在本研究中，我们体外研究了人类肝脏中卡培他滨的代谢。在存在二氢嘧啶脱氢酶抑制剂5-氯-2,4-二羟基吡啶的情况下，研究了人类肝脏S9、微粒体和细胞质中从卡培他滨形成5'-DFCR、5'-DFUR和5-FU的情况。5'-DFCR、5'-DFUR和5-FU在细胞质中以及微粒体和细胞质的组合中从卡培他滨形成。仅在微粒体中检测到5'-DFCR的形成。单独由细胞质以及与微粒体组合催化5-FU形成的表观K(m)和V(max)值分别为8.1 mM和106.5 pmol/min/mg蛋白，以及4.0 mM和64.0 pmol/min/mg蛋白。14个人类肝脏样本中微粒体和细胞质中5'-DFCR形成的个体间差异分别为8.3倍和12.3倍。卡培他滨似乎在人类肝脏中代谢为5-FU。尽管CES位于人类肝脏的微粒体中，但细胞质中5'-DFCR的形成表现出大的个体间差异。在本研究中，已经明确细胞质酶在5'-DFCR形成中是重要的，就像CES一样。

Capecitabine, an anticancer prodrug, is thought to be biotransformed into active 5-fluorouracil (5-FU) by three enzymes. After oral administration, capecitabine is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase (CES), then 5'-DFCR is converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase. 5'-DFUR is activated to 5-FU by thymidine phosphorylase. Although high activities of drug metabolizing enzymes are expressed in human liver, the involvement of the liver in capecitabine metabolism is not fully understood. In this study, the metabolism of capecitabine in human liver was investigated in vitro. 5'-DFCR, 5'-DFUR, and 5-FU formation from capecitabine were investigated in human liver S9, microsomes, and cytosol in the presence of the inhibitor of dihydropyrimidine dehydrogenase, 5-chloro-2,4-dihydroxypyridine. 5'-DFCR, 5'-DFUR, and 5-FU were formed from capecitabine in cytosol and in the combination of microsomes and cytosol. Only 5'-DFCR formation was detected in microsomes. The apparent K(m) and V(max) values of 5-FU formation catalyzed by cytosol alone and in combination with microsomes were 8.1 mM and 106.5 pmol/min/mg protein, and 4.0 mM and 64.0 pmol/min/mg protein, respectively. The interindividual variability in 5'-DFCR formation in microsomes and cytosol among 14 human liver samples was 8.3- and 12.3-fold, respectively. Capecitabine seems to be metabolized to 5-FU in human liver. 5'-DFCR formation was exhibited in cytosol with large interindividual variability, although CES is located in microsomes in human liver. In the present study, it has been clarified that the cytosolic enzyme would be important in 5'-DFCR formation, as is CES.

来源:Hazardous Substances Data Bank (HSDB)

代谢

卡培他滨（Xeloda；CAP）是近期开发的口服抗肿瘤前药，是5-氟尿嘧啶（5-FU）的衍生物，具有增强的肿瘤选择性。以前的研究表明，CAP的激活遵循一个三步酶促反应途径和两个中间代谢物，即5'-脱氧-5-氟胞苷（5'-DFCR）和5'-脱氧-5-氟尿苷（5'-DFUR），在肿瘤组织中优先形成5-FU。在本研究中，调查了大鼠隔离灌注肝脏（IPRL）的肝脏、胆汁和灌注介质以及健康大鼠的肝脏、血浆、肾脏、胆汁和尿液中的所有氟化化合物。此外，来自大鼠尿液的数据与小鼠和人类尿液的数据进行了比较。根据大鼠的低胞苷脱氨酶活性，5'-DFCR在IPRL的灌注介质和大鼠的血浆和尿液中是主要产物。在25至400微摩尔范围内，肝脏和灌注及血浆中循环的5'-DFCR达到相同的浓度值，这支持了es型核苷酸转运体在肝脏中的参与。5'-DFUR和α-氟-β-脲基丙酸（FUPA）+ α-氟-β-丙氨酸（FBAL）是小鼠尿液中的主要产物，占给药剂量的23%至30%，而在大鼠中占3%至4%。在人类尿液中，FUPA + FBAL占给药剂量的50%，5'-DFCR占10%，5'-DFUR占7%。由于氟-19核磁共振光谱学可以全面了解样品中存在的所有氟化化合物，我们观察到了以下未报告的CAP代谢物：1）5-氟胞嘧啶及其羟基代谢物5-氟-6-羟基胞嘧啶，2）氟离子，3）2-氟-3-羟基丙酸和氟乙酸盐，以及4）5'-DFCR的葡萄糖苷酸结合物。

Capecitabine (Xeloda; CAP) is a recently developed oral antineoplastic prodrug of 5-fluorouracil (5-FU) with enhanced tumor selectivity. Previous studies have shown that CAP activation follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-FU preferentially in tumor tissues. In the present work, all fluorinated compounds present in liver, bile, and perfusate medium of isolated perfused rat liver (IPRL) and in liver, plasma, kidneys, bile, and urine of healthy rats /were investigated/. Moreover, data obtained from rat urine were compared with those from mice and human urine. According to a low cytidine deaminase activity in rats, 5'-DFCR was by far the main product in perfusate medium from IPRL and plasma and urine from rats. Liver and circulating 5'-DFCR in perfusate and plasma equilibrated at the same concentration value in the range 25 to 400 microM, which supports the involvement of es-type nucleoside transporter in the liver. 5'-DFUR and alpha-fluoro-beta-ureidopropionic acid (FUPA) + alpha-fluoro-beta-alanine (FBAL) were the main products in urine of mice, making up 23 to 30% of the administered dose versus 3 to 4% in rat. In human urine, FUPA + FBAL represented 50% of the administered dose, 5'-DFCR 10%, and 5'-DFUR 7%. Since fluorine-19 nuclear magnetic resonance spectroscopy gives an overview of all the fluorinated compounds present in a sample, we observed the following unreported metabolites of CAP: 1) 5-fluorocytosine and its hydroxylated metabolite, 5-fluoro-6-hydroxycytosine, 2) fluoride ion, 3) 2-fluoro-3-hydroxypropionic acid and fluoroacetate, and 4) a glucuroconjugate of 5'-DFCR.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟尿嘧啶通过二氢嘧啶脱氢酶代谢为二氢氟尿嘧啶（FUH2），这是一种毒性小得多的代谢物。二氢嘧啶酶切割二氢氟尿嘧啶的嘧啶环，产生5-氟脲基丙酸（FUPA），然后通过β-脲基丙酸酶进一步切割形成α-氟-β-丙氨酸（FBAL）。

Fluorouracil is catabolized to dihydrofluorouracil (FUH2), a much less toxic metabolite, by dihydropyrimidine dehydrogenase. Dihydropyrimidinase cleaves the pyrimidine ring of dihydrofluorouracil, yielding 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by beta-ureido-propionase to form alpha-fluoro-beta-alanine (FBAL).

来源:Hazardous Substances Data Bank (HSDB)

代谢

通过胸苷酸酶代谢成氟尿嘧啶。消除途径：卡培他滨及其代谢物主要经尿液排泄；95.5%的给药剂量在尿液中回收。粪便排泄量极少（2.6%）。尿液中的主要代谢物是FBAL，占给药剂量的57%。大约3%的给药剂量以原药形式经尿液排出。半衰期：卡培他滨及其代谢物的半衰期为45-60分钟。

Metabolized by thymidine phosphorylase to fluoruracil. Route of Elimination: Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose.About 3% of the administered dose is excreted in urine as unchanged drug. Half Life: 45-60 minutes for capecitabine and its metabolites.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

毒性总结

卡培他滨是一种前药，通过胸苷酸磷酸化酶选择性在肿瘤中被激活为其细胞毒性部分，即氟尿嘧啶。氟尿嘧啶在正常细胞和肿瘤细胞内进一步代谢为两种活性代谢物，5-氟-2'-脱氧尿嘧啶一磷酸(FdUMP)和5-氟尿嘧啶三磷酸(FUTP)。FdUMP通过减少正常胸腺嘧啶的产生来抑制DNA合成，而FUTP通过竞争尿嘧啶三磷酸(UTP)来抑制RNA和蛋白质合成。3 卡培他滨的活性部分，氟尿嘧啶，对细胞周期特定阶段（S期）敏感。正常细胞和肿瘤细胞都将5-FU代谢为5-氟-2'-脱氧尿嘧啶一磷酸(FdUMP)和5-氟尿嘧啶三磷酸(FUTP)。这些代谢物通过两种不同的机制引起细胞损伤。首先，FdUMP和叶酸辅因子，N5-10-亚甲基四氢叶酸，与胸苷酸合成酶(TS)结合形成共价结合的三元复合物。这种结合抑制了从2'-脱氧尿嘧啶酸形成胸苷酸。胸苷酸是胸腺嘧啶三磷酸的必需前体，对于DNA的合成至关重要，因此这种化合物的缺乏可以抑制细胞分裂。其次，核转录酶在合成RNA时可能错误地将FUTP代替尿嘧啶三磷酸(UTP)插入。这种代谢错误可能会干扰RNA处理和蛋白质合成。

Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. FdUMP inhibits DNA synthesis by reducing normal thymidine production, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate.3 The active moiety of capecitabine, fluorouracil, is cell cycle phase-specific (Sphase). Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

肝毒性

血清转氨酶升高在传统剂量卡培他滨治疗的病人中占一定比例，但高于正常上限5倍以上的升高不常见，发生的概率是

Serum aminotransferase elevations occur in a proportion of patients on conventional doses of capecitabine therapy, but elevations above 5 times the upper limit of normal are uncommon, occurring in

来源:LiverTox

毒理性

药物性肝损伤

化合物：卡培他滨

Compound:capecitabine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

药物性肝损伤

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

吸收

通过胃肠道容易吸收（约70%）

Readily absorbed through the GI tract (~70%)

来源:DrugBank

吸收、分配和排泄

消除途径

卡培他滨及其代谢物主要经尿液排泄；95.5%的给药剂量在尿液中回收。粪便排泄很少（2.6%）。尿液中排出的主要代谢物是FBAL，占给药剂量的57%。大约3%的给药剂量以未改变的药物形式经尿液排出。

Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose.About 3% of the administered dose is excreted in urine as unchanged drug.

来源:DrugBank

吸收、分配和排泄

卡培他滨易于从胃肠道吸收；平均而言，至少70%的口服剂量被吸收。尽管体外研究表明，在高度酸性条件下卡培他滨不稳定，但药物似乎在溶解后立即被完整吸收，而不会因胃酸的pH值而降解。

Capecitabine is readily absorbed from the GI tract; on average, at least 70% of an oral dose of the drug is absorbed. Although in vitro studies have shown that capecitabine is unstable under highly acidic conditions, the drug appears to be absorbed intact immediately upon dissolution without degradation secondary to the acidic pH of the stomach.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

根据制造商的说法，卡培他滨的血浆峰浓度在大约1.5小时出现，其活性药物氟尿嘧啶的血浆峰浓度稍后在大约2小时出现。

According to the manufacturer, peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil, its active drug, occur slightly later at 2 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在接受了2510毫克/平方米每日剂量的卡培他滨的癌症成人中，该剂量分两次服用，大约在餐后30分钟内，每隔约12小时服用一次，治疗周期第一天的血液样本显示，卡培他滨和氟尿嘧啶的峰值血浆浓度分别在大约2小时内达到3.93和0.66微克/毫升。

In adults with cancer who received a capecitabine dosage of 2510 mg/sq m daily in 2 divided doses, administered approximately 12 hours apart within 30 minutes following the end of a meal, blood samples drawn on day 1 of the treatment cycle showed that peak plasma concentrations of 3.93 and 0.66 ug/mL for capecitabine and fluorouracil, respectively, were achieved in about 2 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

危险品标志：

T
安全说明：

S22,S36/37,S45,S53
危险类别码：

R61,R60,R68,R45
WGK Germany：

3
海关编码：

2934999090
危险品运输编号：

NONH for all modes of transport
RTECS号：

HA3852500
危险标志：

GHS08
危险性描述：

H350,H360FD

卡培他滨 | 154361-50-9

物质功能分类

分子结构分类

物化性质

计算性质

ADMET

安全信息