Lu A Y
Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854-8020, USA.
Drug Metab Dispos. 1998 Dec;26(12):1217-22.
One of the most challenging research areas in pharmacology in the new millennium is to understand why individuals respond differently to drug therapy and to what extent that individual variability in disposition is responsible for the observed differences in therapeutic efficacy and adverse reactions. To answer these complex questions, drug-metabolism research will rely on multidisciplinary approaches more than ever to investigate the many components involved in drug metabolism and disposition. Major research challenges include the following: (1) the genetic variation of drug targets (receptors, enzymes, etc.), drug transporters (multispecific organic anion transporter, P-glycoprotein, alpha-1-acid glycoprotein, etc.), and drug-metabolizing enzymes (cytochrome P450s and other enzymes); (2) the structure and function of all genetic variants of drug receptors, transporters, and metabolizing enzymes; (3) the induction, repression, and inhibition of all components involved in drug disposition; (4) the development of noninvasive in vivo methods to determine the physiological significance of various components in the handling of specific therapeutic agents in humans; (5) the mechanism of idiosyncratic adverse drug reactions; and (6) the pharmacokinetic and pharmacodynamic relationships to explain the individual differences in therapeutic efficacy and drug safety. Thus successful drug-metabolism research in the new millennium must integrate receptor biology, enzymology, recombinant DNA technology, biochemical toxicology, and drug disposition into study design and conduct balanced in vitro and in vivo experiments to allow a full understanding of the mechanisms of individual variability in drug therapy and drug safety.
新千年药理学中最具挑战性的研究领域之一，是理解为何个体对药物治疗的反应不同，以及个体处置差异在多大程度上导致了观察到的治疗效果和不良反应的差异。为回答这些复杂问题，药物代谢研究将比以往任何时候都更依赖多学科方法，以研究药物代谢和处置中涉及的诸多成分。主要研究挑战包括：（1）药物靶点（受体、酶等）、药物转运体（多特异性有机阴离子转运体、P-糖蛋白、α-1-酸性糖蛋白等）和药物代谢酶（细胞色素P450及其他酶）的基因变异；（2）药物受体、转运体和代谢酶所有基因变体的结构和功能；（3）药物处置中所有成分的诱导、抑制和阻遏；（4）开发非侵入性体内方法，以确定人体中处理特定治疗药物时各种成分的生理意义；（5）特异质性药物不良反应的机制；（6）药代动力学和药效学关系，以解释治疗效果和药物安全性方面的个体差异。因此，新千年成功的药物代谢研究必须将受体生物学、酶学、重组DNA技术、生化毒理学和药物处置整合到研究设计中，并进行平衡的体外和体内实验，以便全面理解药物治疗和药物安全性中个体差异的机制。
