Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans
Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans
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DOI：
10.1046/j.1365-2125.1996.00471.x
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发表时间：
1996-12-01
影响因子：
3.4
通讯作者：
Bertilsson, L
中科院分区：
文献类型：
--
作者：
Bottiger, Y;Dostert, P;Bertilsson, L
1尼麦角林是一种麦角衍生物，以前用作血管扩张剂，现已获得治疗老年性痴呆症状的新适应症。2尼麦角林快速水解为醇衍生物1-甲基-10-α-甲氧基-9，10-二氢麦角醇（MMDL），其进一步N-脱甲基化形成10-α-甲氧基-9，10-二氢麦角醇（MDL）。少数个体表现出这种药物的异常代谢，如其形成MDL代谢物的能力降低所示。本研究的目的是确定尼麦角林代谢缺陷是否与异喹和/或S-美芬妥英羟基化多态性相关。3单次口服30 mg尼麦角林后，在15名受试者中研究了其两种代谢产物的血浆浓度，分为三组，就他们的异喹和S-美芬妥英羟化表型。4在10名异喹胍快代谢者中，MMDL和MDL的药代动力学参数相似（其中5人为S-美芬妥英的弱代谢者）（平均MMDL C-max 59 nmol l（-1）和AUC（0，th）144 nmol l（-1）h，平均MDLC-max为183 nmol l（-1），AUC为2627 nmol l（-1）h），但与5名异喹胍代谢不良的受试者有显著差异（平均MMDL C-max 356 nmol l（-1）和AUC 10512 nmol l（-1）h，MDL浓度低于定量限）.5我们得出结论，尼麦角林代谢中MMDL形成MDL在很大程度上由CYP 2D 6催化，观察到的药物代谢模式的个体间差异与异喹有关。羟化多态性
1 Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia.2 Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms.3 After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes.4 The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL C-max 59 nmol l(-1) and AUC (0, th) 144 nmol l(-1) h, mean MDL C-max 183 nmol l(-1) and AUC 2627 nmol l(-1) h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL C-max 356 nmol l(-1) and AUC 10512 nmol l(-1) h, MDL concentrations below limit of quantitation).5 We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.