Biologic risk factors of clinical digoxin toxicity

描述(由申请人提供)：地高辛毒性是导致美国老年人群药物不良事件的常见和重要原因。地高辛的血药浓度和中枢神经系统(CMS)浓度受P-糖蛋白(P-gp)的影响，P-gp调节地高辛的胃肠吸收、肾脏消除和CMS渗透。在临床上接受地高辛治疗的人群中，尚未研究过由基因突变或伴随药物引起的P-gp活性的变化。提高对P-gp在临床地高辛中毒中的作用的了解将有助于阐明中毒的病因，最终可能导致减少地高辛中毒风险的干预措施。这项拟议的病例对照研究的主要目的是在老年患者群体中检查临床地高辛毒性与编码P-gp的多药耐药-1(MDR1)基因的基因型差异之间的关系。第二个目的是表征伴随P-gp抑制活性的药物治疗的效果。除了提高地高辛的安全性外，药物流行病学研究还将促进一名有前途的年轻研究人员的职业发展。通过了解P-gp的生物学特性，这一结果可能会提高几种治疗药物的安全性。

DESCRIPTION (provided by applicant): Digoxin toxicity is a common and important cause of adverse drug events in the elderly US population. The serum and central nervous system (CMS) concentrations of digoxin are affected by p-glycoprotein (P-gp), which regulates gastrointestinal absorption, renal elimination, and CMS penetration of digoxin. The variability in P-gp activity caused by either genetic mutation or concomitant medications has not been studied in a population receiving digoxin clinically. Advancing knowledge of the role of P-gp in clinical digoxin toxicity will assist in elucidating the etiology of toxicity, which may ultimately lead to interventions to reduce the risk of digoxin toxicity. The primary aim of the proposed case-control study is to examine the relationship, in an elderly patient population, between clinical digoxin toxicity and genotypic differences in the multi-drug resistance-1 (MDR1) gene which encodes P-gp. The second aim is to characterize the effect of concomitant drug therapy with P-gp inhibition activity. In addition to improving the safety of digoxin, the - Pharmacoepidemiology study will foster career development in a promising young investigator. The results may advance the safety of several therapeutic agents through understanding the biology of P-gp.