Department of Chemistry, University of Cape Town, Cape Town, South Africa.
Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland.
Drug Discov Today. 2018 Dec;23(12):2023-2030. doi: 10.1016/j.drudis.2018.06.010. Epub 2018 Jun 19.
Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation. TMDD also confounds human microdosing approaches by providing therapeutically unrepresentative PK profiles. Being aware of these phenomena will improve the likelihood of successful drug discovery and development.
在药物发现过程中通常不考虑靶浓度。然而，如果靶标表达浓度相对较高，并且化合物具有高亲和力，以至于大部分药物与靶标结合，那么体外筛选可能会提供化合物亲和力的不可靠信息。在体内，类似的情况会产生与通常预期大相径庭的药代动力学 (PK) 曲线，这是由于靶标结合影响药物分布和清除。小分子的这种靶介导的药物处置 (TMDD) 效应尚未受到太多关注，并且可能仅在临床试验期间才会显现出来，从而有可能导致数据误读。TMDD 还通过提供治疗上无代表性的 PK 曲线来混淆人体微剂量方法。意识到这些现象将提高药物发现和开发成功的可能性。
