Identification of glyburide metabolites formed by hepatic and placental microsomes of humans and baboons
Identification of glyburide metabolites formed by hepatic and placental microsomes of humans and baboons
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DOI：
10.1016/j.bcp.2006.08.024
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发表时间：
2006-12-15
影响因子：
5.8
通讯作者：
Ahmed, Mahmoud S.
中科院分区：
文献类型：
--
作者：
Ravindran, Selvan;Zharikova, Olga L.;Ahmed, Mahmoud S.
格列本脲（格列本脲）是第二代磺脲类药物，用于治疗2型糖尿病和妊娠期糖尿病。迄今为止，已在母体尿液中鉴别出两种格列本脲代谢产物：即4-反式-羟基环己基格列本脲和3-顺式-羟基环己基格列本脲。使用格列本脲治疗妊娠期糖尿病促使我们研究其通过胎盘的代谢。比较了人和狒狒胎盘微粒体制剂的格列本脲代谢与肝脏代谢。采用保留时间、离子电流（在m/z 510处提取）和选择离子监测，通过高效液相色谱-质谱法鉴别了4种组织微粒体形成的代谢物。获得的数据显示，四种微粒体制剂均形成了六种不同的格列本脲羟基化衍生物。然而，由胎盘形成的六种代谢物的量是由肝脏形成的量的一部分。此外，形成的每种代谢物的相对量在种属之间以及两种组织之间不同。此外，通过与合成标准品进行比较，确定了未鉴别代谢物的结构。这些代谢产物被鉴别为4-顺式-羟基环己基格列本脲、3-反式-羟基环己基格列本脲和2-反式-羟基环己基格列本脲。因此，一种格列本脲代谢产物仍有待鉴定，但我们获得的数据使我们能够提出其结构。(c)2006年爱思唯尔公司All rights reserved.
Glyburide (glibenclamide) is a second-generation sulfonylurea used for treatment of type-2 and gestational diabetes mellitus. To date, two glyburide metabolites have been identified in maternal urine: namely, 4-trans-hydroxycyclohexyl glyburide and 3-cis-hydroxycyclohexyl glyburide. The use of glyburide to treat gestational diabetes prompted us to investigate its metabolism by the placenta. The metabolism of glyburide by microsomal preparations from human and baboon placenta was compared with metabolism by their livers. The metabolites formed by the microsomes of the four tissues were identified by high-performance liquid chromatography-mass spectrometry using retention times, ion current (extracted at m/z 510), and selected-ion monitoring. The data obtained revealed the formation of six distinct hydroxylated derivatives of glyburide by each of the four microsomal preparations. However, the amounts of the six metabolites formed by the placentas were a fraction of that formed by the livers. Moreover, the relative quantities of each metabolite formed differed between species as well as between the two tissues. Also, the structure of the unidentified metabolites was determined by comparison with synthesized standards. These metabolites were identified as the 4-cis-hydroxycyclohexyl glyburide, 3-trans-hydroxycyclohexyl glyburide, and 2-trans-hydroxycyclohexyl glyburide. Therefore, one glyburide metabolite remains to be identified, but the data we obtained allowed us to suggest its structure. (c) 2006 Elsevier Inc. All rights reserved.