伊立替康的水解和氧化代谢物,7-ethyl-10 - [4 n - (5-aminopentanoic酸)1-piperidino] carbonyloxycamptothecin和7-ethyl-10 - [4 - (1-piperidino) 1-amino] -carbonyloxycamptothecin,由人类羧酸酯酶CES1A1, CES2,和新表达了羧酸酯酶同工酶,CES3。
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Sanghani SP、Quinney SK Fredenburg结核病,戴维斯WI,聪聪DJ, Bosron WF
伊立替康的水解和氧化代谢物,7-ethyl-10 - [4 n - (5-aminopentanoic酸)1-piperidino] carbonyloxycamptothecin和7-ethyl-10 - [4 - (1-piperidino) 1-amino] -carbonyloxycamptothecin,由人类羧酸酯酶CES1A1, CES2,和新表达了羧酸酯酶同工酶,CES3。
药物金属底座Dispos。2004年5月,32 (5):505 - 11。
- PubMed ID
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15100172 (在PubMed]
- 文摘
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羧酸酯酶代谢酯、硫代酸酯、氨基甲酸酯和酰胺化合物更可溶酸,酒精,和胺产品。他们属于一个基因家族约有50%的序列类之间的身份。beplayappCES1A1和CES2人类同功酶是研究最多的类1和2,分别。在这项研究中,我们报告一个新的人类同工酶的克隆和表达,CES3,属于3班。纯化重组CES3蛋白有羧酸酯酶的活动。羧酸酯酶代谢的氨基甲酸酯前体药物7-ethyl-10 - [4 - (1-piperidino) 1-piperidino] carbonyloxycamptothecin (CPT-11;伊立替康)其活性代谢物7-ethyl-10-hydroxycamptothecin (SN-38),一个强有力的拓扑异构酶抑制剂。CYP3A4氧化CPT-11两个主要氧化代谢物,7-ethyl-10 - [4 n - (5-aminopentanoic酸)1-piperidino] carbonyloxycamptothecin (APC)和7-ethyl-10 - [4 - (1-piperidino) 1-amino] -carbonyloxycamptothecin (NPC)。在这项研究中,我们调查是否这些氧化代谢物,人大和APC,可以通过净化人类的羧酸酯酶,代谢SN-38 CES1A1 CES2, CES3。我们发现CPT-11、APC和人大都可以由羧酸酯酶代谢SN-38。 CES2 has the highest catalytic activity of 0.012 min(-1) microM(-1) among the three carboxylesterases studied for hydrolysis of CPT-11. NPC was an equally good substrate of CES2 in comparison to CPT-11, with a catalytic efficiency of 0.005 min(-1) microM(-1). APC was a very poor substrate for all three isoenzymes, exhibiting a catalytic activity of 0.015 x 10(-3) min(-1) microM(-1) for CES2. Catalytic efficiency of CES3 for CPT-11 hydrolysis was 20- to 2000-fold less than that of CES1A1 and CES2. The relative activity of the three isoenzymes was CES2 > CES1A1 >> CES3, for all three substrates.