Molecular basis of cardiovascular drug metabolism: implications for predicting clinically important drug interactions.
Molecular basis of cardiovascular drug metabolism: implications for predicting clinically important drug interactions.
复制标题
心血管药物代谢的分子基础：对预测临床重要药物相互作用的影响。
DOI：
10.1161/01.cir.101.14.1749
复制
发表时间：
2000
期刊：
影响因子：
37.8
通讯作者：
Flockhart,DA
中科院分区：
文献类型：
--
作者：
Abernethy,DR;Flockhart,DA
与高CYP2D6活性的患者相比，CYP2D6活性表现出更大的ß-肾上腺素能受体阻滞和中枢神经系统副作用。16,17值得注意的是，如果肾脏清除是消除动力学的重要组成部分，CYP2D6对药物消除的贡献可能会被掩盖。这就是氟氯胺的情况，CYP2D618-20基因多态性的文献贡献与药效学无关。在肾功能正常的个体中，未改变的氟氯胺的肾脏清除是一个主要途径。因此，与具有野生型CYP2D6活性的个体相比，只有在肾功能明显下降的患者中，CYP2D6生物转化是清除氟氯胺的主要途径，CYP2D6活性的缺乏才会与清除功能进一步受损相关。大多数药物的生物转化不是由一种特定的CYP酶进行的。苯妥英的生物转化是由CYP2C19和CYP2C9共同催化的。22,23在给定剂量下，任何一种酶活性多态性降低的个体血清苯妥英浓度较高。24,25然而，由于另一种酶对苯妥英蛋白的生物转化有重要作用，因此每种酶的临床影响被稀释了。26 2C9和2C19低活性变异同时存在极为罕见，尚未在临床研究中进行评估。药物与特定CYP酶相互作用的特异性和效力也是确定潜在抑制药物相互作用的临床重要性的核心。例如，强效且特异的CYP3A抑制剂伊曲康唑阻断了阿司咪唑和辛伐他汀两种药物的生物转化，这两种药物都是CYP3A的特异性底物。当伊曲康唑与这两种药物中的任何一种合用时，临床结果可能分别是阿司咪唑诱导的点扭转性心律失常或辛伐他汀诱导的横纹肌溶解。27,28相反，西咪替丁是一种效力较弱且特异性较低的CYP3A抑制剂，与上述两种可能危及生命的药物相互作用均无关。
CYP2D6 activity exhibit markedly greater ß-adrenoceptor blockade and central nervous system side effects than patients with high CYP2D6 activity. 16, 17 Of note, the contribution of CYP2D6 to drug elimination may be obscured if renal clearance is a significant component of elimination kinetics. This is the case with flecainide, for which the documented contribution of the genetic polymorphism in CYP2D618–20 has no pharmacodynamic relevance. Renal clearance of unchanged flecainide is a major pathway in individuals with normal renal function. Therefore, only in patients with markedly decreased renal function in whom flecainide biotransformation by CYP2D6 is a major route of clearance would the absence of CYP2D6 activity be associated with further impairment of elimination compared with individuals with wild-type CYP2D6 activity. 21 The biotransformation of most drugs is not carried out by one specific CYP enzyme. Phenytoin biotransformation is catalyzed by both CYP2C19 and CYP2C9. 22, 23 Individuals with polymorphically decreased activity of either enzyme have higher serum phenytoin concentration at a given dose. 24, 25 The clinical impact of each individual enzyme is diluted, however, because the other enzyme contributes significantly to phenytoin biotransformation. 26 The coincident presence of both 2C9 and 2C19 low-activity variants is extremely rare and has not been evaluated in clinical study. The specificity and potency of the interaction of a drug with a particular CYP enzyme is also central to the definition of the clinical importance of potential inhibitory drug interactions. For example, the potent and specific CYP3A inhibitor itraconazole blocks the biotransformation of 2 drugs, astemizole and simvastatin, each of which is a very specific substrate for CYP3A. When itraconazole is coadministered with either of these drugs, the clinical result may be astemizole-induced torsade de pointes arrhythmia or simvastatin-induced rhabdomyolysis, respectively. 27, 28 In contrast, cimetidine, a less potent and less specific CYP3A inhibitor, is associated with neither of these potentially life-threatening drug interactions.
登录
查看更多内容
DOI：
--
发表时间：
1996-04
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
K. Kunze;L. Wienkers;K. Thummel;W. Trager
通讯作者：
K. Kunze;L. Wienkers;K. Thummel;W. Trager
心律失常患者慢性氟卡尼和奎尼丁之间的立体选择性遗传决定相互作用。
影响因子：
3.4
作者：
Birgersdotter,UM;Wong,W;Turgeon,J;Roden,DM
通讯作者：
Roden,DM
影响因子：
37.8
作者：
SIDDOWAY, LA;THOMPSON, KA;WOOSLEY, RL
通讯作者：
WOOSLEY, RL
DOI：
--
发表时间：
1996-12
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
M. Bajpai;L. Roskos;D. Shen;R. Levy
通讯作者：
M. Bajpai;L. Roskos;D. Shen;R. Levy
DOI：
10.1097/00008571-199710000-00004
发表时间：
1997-10
期刊：
Pharmacogenetics
影响因子：
--
作者：
D. J. Steward;R. Haining;K. Henne;G. Davis;T. Rushmore;W. Trager;A. Rettie
通讯作者：
D. J. Steward;R. Haining;K. Henne;G. Davis;T. Rushmore;W. Trager;A. Rettie