双胍类抗疟药氯胍的激活与美芬妥因氧化多态性共分离——一项分组研究。
The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism--a panel study.
作者信息
Ward S A, Helsby N A, Skjelbo E, Brøsen K, Gram L F, Breckenridge A M
机构信息
Department of Parasitology, Liverpool School of Tropical Medicine.
出版信息
Br J Clin Pharmacol. 1991 Jun;31(6):689-92. doi: 10.1111/j.1365-2125.1991.tb05594.x.
Abstract
The activation of the antimalarial drug proguanil (PG) to the active metabolite cycloguanil (CG) has been evaluated in a panel of 18 subjects. These subjects had previously been screened and classified as mephenytoin poor (PMm) or extensive metabolisers (EMm) and sparteine poor (PMs) or extensive metabolisers (EMs). Five subjects had the phenotype PMm/EMs, one was PMm/PMs, six subjects were EMm/PMs and six were EMm/EMs. The PG/CG ratio in urine (8 h) was significantly higher in PMm than in EMm (P = 0.0013). This study shows that the P450-isozyme involved in the polymorphic oxidation of mephenytoin is of critical importance in the activation of PG to CG and this may explain the large intersubject variability in CG concentrations in man. PMm make up about 3% of Caucasians, but up to about 20% of Orientals. From the present study, it may be anticipated that the antimalarial effect of PG is absent or impaired in this phenotype. The sparteine polymorphism appeared not to influence the activation of PG to CG significantly.
摘要
已在一组18名受试者中评估了抗疟药氯胍（PG）向活性代谢产物环氯胍（CG）的活化情况。这些受试者先前已接受筛查，并被分类为美芬妥因慢代谢者（PMm）或快代谢者（EMm）以及司巴丁慢代谢者（PMs）或快代谢者（EMs）。5名受试者具有PMm/EMs表型，1名是PMm/PMs，6名受试者是EMm/PMs，6名是EMm/EMs。PMm受试者尿液中（8小时）的PG/CG比值显著高于EMm受试者（P = 0.0013）。这项研究表明，参与美芬妥因多态性氧化的P450同工酶在PG向CG的活化中至关重要，这可能解释了人体中CG浓度存在较大个体间差异的原因。PMm在高加索人中约占3%，但在东方人中高达约20%。从本研究可以预期，PG在该表型中的抗疟作用不存在或受损。司巴丁多态性似乎对PG向CG的活化没有显著影响。
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