作用的肝代谢bioactivation和阿莫地喹的解毒作用。

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朱厄尔H,马格斯杰,哈里森AC,奥尼尔点,BK Ruscoe我,公园

作用的肝代谢bioactivation和阿莫地喹的解毒作用。

Xenobiotica。1995年2月,25 (2):199 - 217。

PubMed ID

7618347 (在PubMed

]

文摘

1。肝代谢的抗疟药物阿莫地喹调查以获得进一步了解代谢的因果关系假设肝毒性,限制药物的使用。后intraportal (i.p)政府(54 mumol /公斤)麻醉大鼠,胆汁中的药物排泄(23 + / - 3%剂量超过5 h;意思是+ / - SD, n = 6)主要是硫醚配合。2。ip管理后,20%的剂量是汇聚成24小时尿N-dealkylation母体化合物和产品、氧化脱氨基作用。Desethylamodiaquine堆积在肝脏,但不是一个衬底bioactivation以消除胆道谷胱甘肽的加合物。3所示。酮康唑管理之前,P450酶的抑制剂,胆汁排泄减少了50%,影响相应减少药物不可逆转地绑定到肝脏的蛋白质。这表示一个角色P450的bioactivation阿莫地喹轭合物的活性代谢物与谷胱甘肽和蛋白质。 4. De-ethylation and irreversible binding were observed in vitro using male rat liver microsomes, and were again inhibited by ketoconazole. However, no such binding was observed with human (six individuals) hepatic microsomes despite extensive turnover of amodiaquine to desethylamodiaquine. 5. Amodiaquine quinoneimine underwent rapid reduction in the presence of either human or rat liver microsomes. Therefore in vitro studies may underestimate the bioactivation of amodiaquine in vivo. These data indicate that the extent of protein adduct formation in the liver will depend on the relative rates of oxidation of amodiaquine and reduction of its quinoneimine. This in turn may be a predisposing factor in the idiosyncratic hepatotoxicity associated with amodiaquine. 6. Substitution of a fluorine for the phenolic hydroxyl group in amodiaquine blocked bioactivation of the drug in vivo. Insertion of an N-hydroxyethyl function enabled partial clearance of amodiaquine and its deshydroxyfluoro analogue via O-glucuronidation and altered the balance between phase I oxidation and direct phase II conjugation of amodiaquine.

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药物

阿莫地喹