Rodrigues A D, Roberts E M
Merck Research Laboratories, West Point, PA 19486-0004, USA.
Drug Metab Dispos. 1997 May;25(5):651-5.
The effect of dexmedetomidine DEX on cytochrome P4502D6 (CYP2D6)-dependent dextromethorphan O-demethylase (DEXTROase) activity was studied using native human liver microsomes. DEX (0.01-4.0 microM inhibited DEXTROase activity (IC50 = 1.8 +/- 0.25 microM; mean +/- SD; N = 5 livers) and was less potent than quinidine (QND), prototypical and clinically relevant CYP2D6 inhibitor (IC50 = 0.22 +/- 0.02 microM; mean Ki = 0.07 microM). Similar results were obtained with human B-lymphoblast microsomes containing cDNA-expressed CYP2D6 (DEX, IC50 = 2.2 microM; QND, IC50 0.15 microM). Formal kinetic analyses indicated that DEX was a reversible mixed (competitive/noncompetitive) inhibitor of DEXTROase activity in human liver microsomes, where Kies > Ki and alpha > 1 (Ki = 0.4 +/- 0.2 microM; Kies = 2.3 +/- 0.9 microM; alpha = 8.1 +/- 6.8; N = 3 livers). In addition, DEX elicited a Type IIb difference spectrum (lambda max approximately 436 nm; lambda min approximately 414 nm) when added to cDNA-expressed CYP2D6 under aerobic (oxidized) conditions. These data indicated that DEX was able to bind reversibly to the heme (ferric) iron of CYP2D6. It is postulated that binding occurs via the 4(5)-substituted imidazole moiety. In this instance, binding was characterized by a spectral dissociation constant (Ks) of 0.4 microM that was identical to the Ki obtained with native human liver microsomes.
使用原代人肝微粒体研究了右美托咪定（DEX）对细胞色素P4502D6（CYP2D6）依赖性右美沙芬O - 脱甲基酶（DEXTROase）活性的影响。DEX（0.01 - 4.0微摩尔）抑制了DEXTROase活性（IC50 = 1.8±0.25微摩尔；平均值±标准差；N = 5个肝脏），其效力低于原型且具有临床相关性的CYP2D6抑制剂奎尼丁（QND）（IC50 = 0.22±0.02微摩尔；平均Ki = 0.07微摩尔）。在含有cDNA表达的CYP2D6的人B淋巴细胞微粒体中也获得了类似结果（DEX，IC50 = 2.2微摩尔；QND，IC50 = 0.15微摩尔）。正式的动力学分析表明，DEX是人类肝微粒体中DEXTROase活性的可逆混合（竞争性/非竞争性）抑制剂，其中Kies> Ki且α> 1（Ki = 0.4±0.2微摩尔；Kies = 2.3±0.9微摩尔；α = 8.1±6.8；N = 3个肝脏）。此外，在需氧（氧化）条件下将DEX添加到cDNA表达的CYP2D6中时，会产生IIb型差示光谱（λmax约为436纳米；λmin约为414纳米）。这些数据表明DEX能够与CYP2D6的血红素（铁）铁可逆结合。据推测，结合是通过4（5） - 取代的咪唑部分发生的。在这种情况下，结合的特征在于光谱解离常数（Ks）为0.4微摩尔，这与用原代人肝微粒体获得的Ki相同。
