The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin
The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin
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DOI：
10.1124/dmd.31.1.53
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发表时间：
2003-01-01
影响因子：
3.9
通讯作者：
Waskell, LA
中科院分区：
文献类型：
--
作者：
Clarke, TA;Waskell, LA
前药氯吡格雷（Plavidine）被细胞色素P450（P450）活化为抑制ADP诱导的血小板聚集的代谢物。氯吡格雷经常与CYP 3A 4底物阿托伐他汀（立普妥）联合给药。由于临床研究表明阿托伐他汀抑制氯吡格雷的抗血小板活性，我们研究了CYP 3A 4是否在体外代谢氯吡格雷。从地塞米松预处理大鼠制备的微粒体代谢氯吡格雷的速率为3.8 nmol min（-1）nmol P450（-1），分别比对照组和β-萘酮处理大鼠的微粒体代谢速率快65%和1270%。为了鉴定负责氯吡格雷氧化的人P450，检测了含有单一人P450同工酶的基因工程微粒体氧化氯吡格雷的能力。CYP 3A 4和3A 5代谢氯吡格雷的速率显著高于其他8种P450同工酶，表明CYP 3A 4和3A 5主要负责体内氯吡格雷代谢。氯吡格雷与人CYP 3A 4相互作用的光谱解离常数（K-s）、K-m和V-max分别为12 μ M、14 +/- 1 μ M和6.7 +/- 1 nmol min（-1）nmol P450（-1）。阿托伐他汀内酯，生理相关底物，抑制氯吡格雷，Ki为6 μ M。当氯吡格雷和阿托伐他汀以等摩尔浓度存在时，氯吡格雷代谢被抑制90%以上。由于CYP 3A 4和3A 5代谢氯吡格雷的速度比其他人P450同工酶快，并且是人肝脏中最丰富的P450，因此预计它们主要负责体内氯吡格雷的活化。
The prodrug clopidogrel (Plavix) is activated by cytochrome P450 (P450) to a metabolite that inhibits ADP-induced platelet aggregation. Clopidogrel is frequently administered to patients in conjunction with the CYP3A4 substrate atorvastatin (Lipitor). Since clinical studies indicate that atorvastatin inhibits the antiplatelet activity of clopidogrel, we investigated whether CYP3A4 metabolized clopidogrel in vitro. Microsomes prepared from dexamethasone-pretreated rats metabolized clopidogrel at a rate of 3.8 nmol min(-1) nmol of P450(-1), which is 65 and 1270% faster than the rate of metabolism by microsomes from control and beta-napthoflavone-treated rats, respectively. To identify the human P450s responsible for clopidogrel oxidation, genetically engineered microsomes containing a single human P450 isozyme were tested for their ability to oxidize clopidogrel. CYP3A4 and 3A5 metabolized clopidogrel at a significantly higher rate than eight other P450 isozymes, suggesting that CYP3A4 and 3A5 are primarily responsible for in vivo clopidogrel metabolism. Clopidogrel interacts with human CYP3A4 with a spectral dissociation constant (K-s), K-m, and V-max of 12 muM, 14 +/- 1 muM and 6.7 +/- 1 nmol min(-1) nmol P450(-1), respectively. Atorvastatin lactone, the physiologically relevant substrate, inhibits clopidogrel with a K-i of 6 muM. When clopidogrel and atorvastatin are present at equimolar concentrations, clopidogrel metabolism is inhibited by greater than 90%. Since CYP3A4 and 3A5 metabolize clopidogrel faster than other human P450 isozymes and are the most abundant P450s in human liver, they are predicted to be predominantly responsible for the activation of clopidogrel in vivo.