吡喹酮对映异构体在诱导和未诱导大鼠肝微粒体内代谢的立体选择性  

Stereoselective metabolism of praziquantel enantiomers in rat liver microsomes with and without of cytochrome P450 inducers

作　　者：张渝娟[1] 全钰珠[1] 邱宗荫[1] 

机构地区：[1]重庆医科大学药理教研室

出　　处：《中国药理学与毒理学杂志》1996年第1期62-66,共5页Chinese Journal of Pharmacology and Toxicology

摘　　要：吡喹酮（ＰＱＴ）对映异构体在未诱导大鼠肝微粒体内仅（－）ＰＱＴ生成一个主要代谢产物－ＲｉｎｇＤ－ＯＨ，而在β－萘黄酮（β－ＮＦ）诱导的大鼠肝微粒体内两者均生成ＲｉｎｇＤ－ＯＨ．（＋）ＰＱＴ在苯巴比妥（ＰＢ）诱导的肝微粒体内可生成三个主要代谢物，即ＲｉｎｇＤ－ＯＨ，ＲｉｎｇＢ－ＯＨ和ＲｉｎｇＡ－ＯＨ，而（－）ＰＱＴ仅生成ＲｉｎｇＤ－ＯＨ和ＲｉｎｇＡ－ＯＨ．在地塞米松（ＤＥＸ）诱导的大鼠肝微粒体内，ＰＱＴ对映异构体代谢后生成四个主要产物，除ＲｉｎｇＤ－ＯＨ，ＲｉｎｇＢ－ＯＨ和ＲｉｎｇＡ－ＯＨ外，尚有ＲｉｎｇＤ，Ｂ－２ＯＨ．ＰＱＴ对映异构体无论在β－ＮＦ，ＰＢ或ＤＥＸ诱导的肝微粒体内，ＲｉｎｇＤ－ＯＨ的生成速率均为（－）ＰＱＴ大于（＋）ＰＱＴ，ＲｉｎｇＢ－ＯＨ和ＲｉｎｇＡ－ＯＨ的生成均为（＋）ＰＱＴ较（－）ＰＱＴ优先被羟化．本实验结果表明，β－ＮＦ，ＰＢ和ＤＥＸ所诱导的ＣＹＰ１Ａ，ＣＹＰ２Ｂ和ＣＹＰ３Ａ及未诱导Ｐ４５０代谢ＰＱＴ对映异构体表现出完全的或部分的立体选择性．In untreated rat liver microsomes, only Ring D-OH was formed from (-)PQT, while in rat liver microsomes with pretreatment of β-NF, both PQT enantiomers were metabolized to form the same major product, the Ring D-OH. The ratio of (-)/(+)PQT for this monohydroxylate formation rate was 3 4±0 5 (x±s). In liver microsomes induced by PB, (+)PQT was metabolized to form three major metabolites which were Ring D-OH, Ring B-OH and Ring A-OH, while (-)PQT was metabolized only to form Ring D-OH and Ring A-OH, and Ring B-OH was almost not detectable from HPLC. The ratio of (-)/(+)PQT for Ring D-OH and Ring A-OH formation rate was 3 04±0 09 and 0 6±0 01, respectively. In liver microsomes pretreated with DEX, PQT enantio- mer metabolized to form four major metabolites. They were Ring D,B-2OH, Ring D-OH, Ring B-OH and Ring A-OH. The formation rate of dihydroxylated metabolite and Ring D-OH from (-)PQT was 1 64±0 11 fold and 1 7±0 3 fold, respectively, as that from (+)PQT. The ratio of (-)/(+)PQT for Ring B-OH and Ring A-OH formation rate was 0 34±0 04 and 0 78±0 07, respectively. These results indicated that the uninduced P450 and CYP1A, CYP2B or CYP3A induced by β-NF, PB or DEX, respectively catalized the hydroxylation of PQT D ring, B ring and A ring moiety in a manner of partial or complete chiral stereoselectivity.

关 键 词：异构体 吡喹酮 抗蠕虫药 肝 代谢 立体选择性 

分 类 号：R978.63[医药卫生—药品] R969.1[医药卫生—药学]