KETAMINE AS A PROBE FOR MEDETOMIDINE STEREOISOMER INHIBITION OF HUMAN LIVER MICROSOMAL DRUG-METABOLISM
KETAMINE AS A PROBE FOR MEDETOMIDINE STEREOISOMER INHIBITION OF HUMAN LIVER MICROSOMAL DRUG-METABOLISM
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DOI：
10.1097/00000542-199212000-00023
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发表时间：
1992-12-01
期刊：
影响因子：
8.8
通讯作者：
LABROO, R
中科院分区：
文献类型：
--
作者：
KHARASCH, ED;HERRMANN, S;LABROO, R
美托咪定（MED）是一种新型、选择性α 2肾上腺素能激动剂，具有强效镇静、催眠和镇痛作用，目前正在作为麻醉辅助剂进行评价。MED的药理作用是立体特异性的，完全是由于D-异构体（DMED），而L-异构体（LMED）基本上是无活性的。DMED是一种4（5）取代的咪唑，已显示可抑制肾上腺类固醇生成和人肝微粒体阿芬太尼代谢（细胞色素P-450介导的反应）。MED抑制细胞色素P-450的机制尚不清楚。本研究的目的是确定DMED抑制人细胞色素P-450介导的微粒体代谢的机制，使用氯胺酮作为探针。氯胺酮经历了广泛的肝脏生物转化，以前曾用于表征咪唑麻醉剂对人P-450催化的药物代谢的影响。采用气相色谱-质谱联用选择离子监测法测定了三种人肝微粒体对氯胺酮N-去甲基化的影响。DMED是S（+）氯胺酮N-脱甲基化的有效竞争性抑制剂，对于高亲和力氯胺酮脱甲基酶的K（i）为0.11 - 0.18 μ M。治疗浓度的外消旋氯胺酮（10 μ M）的DMED抑制的IC 50为0.15 +/-0.02 μ M。在加入氯胺酮之前，DMED与微粒体和NADPH生成系统的预孵育对氯胺酮脱甲基酶活性的抑制没有额外的影响，因此表明母体化合物而不是DMED代谢产物是抑制性物质。LMED虽然对氯胺酮无活性，但在治疗浓度下对外消旋氯胺酮和氯胺酮对映体去甲基化具有比DMED更大的抑制作用。光谱研究表明，DMED与微粒体细胞色素P-450相互作用，引起II型结合谱。这些结果表明，DMED是细胞色素P-450催化活性的有效抑制剂，通过直接结合P-450血红素铁和在底物结合位点的竞争性抑制来抑制氯胺酮去甲基化。与异构体混合物相比，DMED在同等有效浓度下发生药物相互作用的可能性较小。
Medetomidine (MED) is a novel, selective, alpha2 adrenergic agonist with potent sedative, hypnotic, and analgesic properties, currently undergoing evaluation as an anesthetic adjuvant. The pharmacologic effects of MED are stereospecific, due entirely to the D-isomer (DMED), whereas the L-isomer (LMED) is essentially inactive. DMED, a 4(5)substituted imidazole, has been shown to inhibit adrenal steroidogenesis and human liver microsomal alfentanil metabolism, reactions mediated by cytochrome P-450. The mechanism of MED inhibition of cytochrome P-450 is unknown. The purpose of this investigation was to determine the mechanism of DMED inhibition of human cytochrome P-450-mediated microsomal metabolism, using ketamine as a probe. Ketamine undergoes extensive hepatic biotransformation and has been used previously to characterize the effects of imidazole anesthetics on human P-450-catalyzed drug metabolism. Ketamine N-demethylation by microsomes from three human livers was measured by gas chromatography-mass spectrometry with selected-ion monitoring. DMED was a potent, competitive inhibitor of S(+) ketamine N-demethylation, with a K(i) of 0.11-0.18 muM for the high affinity ketamine demethylase. The IC50 for DMED inhibition of therapeutic concentrations of racemic ketamine (10 muM) was 0.15 +/- 0.02 muM. Preincubation of DMED with microsomes and an NADPH generating system prior to ketamine addition had no additional effect on the inhibition of ketamine demethylase activity, thereby implicating the parent compound rather than a DMED metabolite as the inhibitory species. LMED, although pharmacologically inactive, had a greater inhibitory effect than DMED on racemic ketamine and ketamine enantiomer demethylation at therapeutic concentrations. Spectral studies showed that DMED interacted with microsomal cytochrome P-450 to elicit a Type II binding spectrum. These results demonstrate that DMED is a potent inhibitor of cytochrome P-450 catalytic activity, inhibiting ketamine demethylation by direct binding to P-450 heme iron and competitive inhibition at the substrate binding site. DMED, compared to the mixture of isomers, has a lesser potential for drug interactions at equally effective concentrations.