Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine.
Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine.
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人肝微粒体体外非那西丁 O-去乙基化：化学探针、SSRI 抗抑郁药、奈法唑酮和文拉法辛的抑制。
DOI：
10.1007/s002130050149
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发表时间：
1996
影响因子：
3.4
通讯作者：
Shader,RI
中科院分区：
文献类型：
--
作者：
vonMoltke,LL;Greenblatt,DJ;Duan,SX;Schmider,J;Kudchadker,L;Fogelman,SM;Harmatz,JS;Shader,RI
在一系列人类肝脏的微粒体制剂中研究了非那西丁通过 O-脱乙基作用生物转化为对乙酰氨基酚，这是反映细胞色素 P450-1A2 活性的指标反应。对乙酰氨基酚的形成与双 Michaelis-Menten 系统一致，具有低 Km（平均 Km1= 68 μM）和高 Km（平均 Km2= 7691 μM）成分。低 Kmenzyme 平均占估计内在清除率的 96%，并且预计在非那西丁浓度低于 2000μM 时贡献超过 50% 的净反应速度。在指标抑制剂探针中，α-萘黄酮是低Kmenzyme的高效抑制剂（Ki1= 0.013 μM）；呋拉茶碱也是一种中等活性的抑制剂（Ki1= 4.4 μM），但其抑制效力通过与微粒体预孵育而增加。酮康唑是一种相对较弱的抑制剂（Ki1= 32 μM）；奎尼丁和西咪替丁显示出最小的抑制活性。在六种选择性血清素再摄取抑制剂 (SSRI) 抗抑郁药中，氟伏沙明是 1A2 的有效抑制剂（平均 Ki1= 0.24 μM）。其他 SSRIs 的效力要低十倍以上。平均 Ki1 值为：氟西汀，4.4 μM；去甲氟西汀，15.9 μM；舍曲林，8.8 μM；去甲基舍曲林，9.5μM；帕罗西汀，5.5 μM。抗抑郁药奈法唑酮及其四种代谢物（间氯苯基哌嗪、两种羟基化衍生物和一种三唑二酮）是 P450-1A2 的非常弱的抑制剂。文拉法辛及其 O- 和 N- 去甲基代谢物显示出最小的抑制活性。
Biotransformation of phenacetin viaO-deethylation to acetaminophen, an index reaction reflecting activity of Cytochrome P450-1A2, was studied in microsomal preparations from a series of human livers. Acetaminophen formation was consistent with a double Michaelis-Menten system, with low-Km(mean Km1= 68 μM) and high-Km(mean Km2= 7691 μM) components. The low-Kmenzyme accounted for an average of 96% of estimated intrinsic clearance, and was predicted to contribute more than 50% of net reaction velocity at phenacetin concentrations less than 2000 μM. Among index inhibitor probes, α-naphthoflavone was a highly potent inhibitor of the low-Kmenzyme (Ki1= 0.013 μM); furafylline also was a moderately active inhibitor (Ki1= 4.4 μM), but its inhibiting potency was increased by preincubation with microsomes. Ketoconazole was a relatively weak inhibitor (Ki1= 32 μM); quinidine and cimetidine showed minimal inhibiting activity. Among six selective serotonin reuptake inhibitor (SSRI) antidepressants, fluvoxamine was a potent inhibitor of 1A2 (mean Ki1= 0.24 μM). The other SSRIs were more than tenfold less potent. Mean Ki1values were: fluoxetine, 4.4 μM; norfluoxetine, 15.9 μM; sertraline, 8.8 μM; desmethylsertraline, 9.5μM; paroxetine, 5.5 μM. The antidepressant nefazodone and four of its metabolites (meta-chloro-phenylpiperazine, two hydroxylated derivatives, and a triazoledione) were very weak inhibitors of P450-1A2. Venlafaxine and itsO- andN-desmethyl metabolites showed minimal inhibitory activity.