霉酚酸吗啉乙酯 - CAS号 128794-94-5

物化性质

熔点：

95-96°C
沸点：

637.6±55.0 °C(Predicted)
密度：

1.222±0.06 g/cm3(Predicted)
溶解度：

在DMSO中的溶解度≥15mg/mL
物理描述：

Solid
颜色/状态：

White to off-white crystalline powder
蒸汽压力：

1.9X10-13 mm Hg at 25 °C (est)
解离常数：

pKa1 = 5.6 (tertiary amine); pKa2 = 8.5 (phenol)
碰撞截面：

197.3 Å² [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

辛醇/水分配系数(LogP)：

3.2
重原子数：

31
可旋转键数：

10
环数：

3.0
sp3杂化的碳原子比例：

0.57
拓扑面积：

94.5
氢给体数：

1
氢受体数：

8

ADMET

代谢

吗替麦考酚酯（Mycophenolate Mofetil，MMF）在口服和静脉给药后，完全由肝脏的羧酸酯酶1和2代谢为活性母药麦考酚酸（Mycophenolic Acid，MPA）。随后，MPA通过葡萄糖醛酸转移酶的酶作用，代谢产生无活性的MPA酚葡萄糖苷酸（MPAG）。葡萄糖苷酸代谢物很重要，因为它可以通过肠肝循环转化为MPA。在肠道中逃脱代谢的吗替麦考酚酯通过门静脉进入肝脏，在肝细胞中转化为药理活性的MPA。N-(2-羧甲基)-吗啉、N-(2-羟基乙基)-吗啉以及N-(2-羟基乙基)-吗啉的N-氧化物部分是MMF在肠道中由于肝脏羧酸酯酶2活性产生的额外代谢物。除了其他也参与MPA代谢的UGT酶外，肝脏中的UGT1A9和UGT2B7是MPA代谢的主要酶。MPA的四个主要代谢物是7-O-MPA-β-葡萄糖苷酸（MPAG，无活性），通过尿苷5ʹ-二磷酸葡萄糖醛酸基转移酶（UGT）活性产生的MPA酰基葡萄糖苷酸（AcMPAG），通过UGT产生的7-O-MPA葡萄糖苷，以及通过CYP3A4/5和CYP2C8酶产生的少量6-O-去甲基-MPA（DM-MPA）。

After both oral and intravenous administration mycophenolate mofetil is entirely metabolized by liver carboxylesterases 1 and 2 to mycophenolic acid (MPA), the active parent drug. It is then metabolized by the enzyme glucuronyl transferase, producing the inactive phenolic glucuronide of MPA (MPAG). The glucuronide metabolite is important, as it is then converted to MPA through enterohepatic recirculation. Mycophenolate mofetil that escapes metabolism in the intestine enters the liver via the portal vein and is transformed to pharmacologically active MPA in the liver cells.N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide portion of N-(2-hydroxyethyl)-morpholine are additional metabolites of MMF occurring in the intestine as a result of liver carboxylesterase 2 activity. UGT1A9 and UGT2B7 in the liver are the major enzymes contributing to the metabolism of MPA in addition to other UGT enzymes, which also play a role in MPA metabolism. The four major metabolites of MPA are 7-O-MPA-β-glucuronide (MPAG, inactive), MPA acyl-glucuronide (AcMPAG), produced by uridine 5ʹ-diphosphate glucuronosyltransferases (UGT) activities, 7-O-MPA glucoside produced via UGT, and small amounts 6-O-des-methyl-MPA (DM-MPA) via CYP3A4/5 and CYP2C8 enzymes.

来源:DrugBank

代谢

在口服和静脉给药后，吗替麦考酚酯（mycophenolate mofetil）完全代谢为活性代谢物MPA（麦考酚酸/mycophenolic acid）。口服给药后，MPA的代谢发生在系统前。MPA主要通过葡萄糖苷酸转移酶代谢，形成MPA的酚葡萄糖苷酸（MPAG），后者无药理活性。在体内，MPAG通过肠肝循环转化为MPA。在健康受试者口服吗替麦考酚酯后，还能在尿液中回收2-羟基乙基-吗啉基团的以下代谢物：N-(2-羧甲基)-吗啉、N-(2-羟基乙基)-吗啉和N-(2-羟基乙基)-吗啉的N-氧化物。

Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA /mycophenolic acid/, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2- hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2- hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

药物性肝损伤

化合物：吗替麦考酚酯

Compound:mycophenolate mofetil