Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide.
Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide.
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DOI：
10.1016/j.bcp.2009.08.003
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发表时间：
2009-12-15
影响因子：
5.8
通讯作者：
Ahmed, Mahmoud S.
中科院分区：
文献类型：
--
作者：
Zharikova, Olga L.;Fokina, Valentina M.;Nanovskaya, Tatiana N.;Hill, Ronald A.;Mattison, Donald R.;Hankins, Gary D. V.;Ahmed, Mahmoud S.
影响药物孕期药代动力学(PK)的因素之一是肝脏和胎盘代谢酶的活性。最近，我们报道了人肝和胎盘微生物体将格列本脲生物转化为六种结构相同的代谢物。其中两种代谢物，4-反式-(M1)和3-顺式-羟基环己基格列本脲(M2B)，先前在接受格列本脲治疗的患者的血浆和尿中被发现，并具有药理活性。这项研究的目的是确定导致格列本脲每种代谢物形成的主要人体肝脏和胎盘细胞色素P450同工酶。这是通过使用针对单个CYP同工酶的选择性化学抑制剂和针对它们的抗体来实现的。基因表达的酶对格列本脲的生物转化动力学常数证实了这一点。结果表明，肝脏各代谢物形成的主要同工酶如下：CYP3A4(乙烯-羟基格列本脲(M5)、3-反式(M3)和2-反式(M4)格列本脲)；CYP2C9(M1、M2a(4-cis-)和M2B)；人胎盘微粒体细胞色素P19/芳香酶是格列本脲生物转化为主要的M5的主要同工酶。胎盘中大量的M5由细胞色素PYP19形成，可以使这种代谢物更容易进入胎儿的血液循环。生物转化格列本脲的酶和形成的代谢物的多样性突显了其在体内与药物相互作用的潜力。
One of the factors affecting the pharmacokinetics (PK) of a drug during pregnancy is the activity of hepatic and placental metabolizing enzymes. Recently, we reported on the biotransformation of glyburide by human hepatic and placental microsomes to six metabolites that are structurally identical between the two tissues. Two of the metabolites, 4-trans- (M1) and 3-cis-hydroxycyclohexyl glyburide (M2b), were previously identified in plasma and urine of patients treated with glyburide and are pharmacologically active. The aim of this investigation was to identify the major human hepatic and placental CYP450 isozymes responsible for the formation of each metabolite of glyburide. This was achieved by the use of chemical inhibitors selective for individual CYP isozymes and antibodies raised against them. The identification was confirmed by the kinetic constants for the biotransformation of glyburide by cDNA-expressed enzymes. The data revealed that the major hepatic isozymes responsible for the formation of each metabolite are as follows: CYP3A4 (ethylene-hydroxylated glyburide (M5), 3-trans-(M3) and 2-trans-(M4) cyclohexyl glyburide); CYP2C9 (M1, M2a( 4-cis-) and M2b); CYP2C8 (M1 and M2b); and CYP2C19 (M2a). Human placental microsomal CYP19/aromatase was the major isozyme responsible for the biotransformation of glyburide to predominantly M5. The formation of significant amounts of M5 by CYP19 in the placenta could render this metabolite more accessible to the fetal circulation. The multiplicity of enzymes biotransforming glyburide and the metabolites formed underscores the potential for its drug interactions in vivo.
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影响因子：
9.8
作者：
Jacobson, GF;Ramos, GA;Field, DR
通讯作者：
Field, DR
DOI：
10.1124/jpet.103.053199
发表时间：
2003-09-01
影响因子：
3.5
作者：
Deshmukh, SV;Nanovskaya, TN;Ahmed, MS
通讯作者：
Ahmed, MS
影响因子：
5.8
作者：
Nanovskaya, TN;Deshmukh, SV;Ahmed, MS
通讯作者：
Ahmed, MS
影响因子：
5.8
作者：
Ravindran, Selvan;Zharikova, Olga L.;Ahmed, Mahmoud S.
通讯作者：
Ahmed, Mahmoud S.
影响因子：
2.9
作者：
BALANT, L;FABRE, J;ZAHND, GR
通讯作者：
ZAHND, GR