基于性质的药物设计 药物的药物动力学是药物的宏观性质在吸收、 分布、代谢和排泄上的反映 基于性质的药物设计(PBDD)指的是针对药物或 药物候选物结构进行药动学性质设计与优化,以 实现药物或药物候选物的良好口服吸收、定向分 布、可控代谢、优化消除或降低毒副作用的目的 性质是药物分孑的宏观与微观结构的综合反映
基于性质的药物设计 • 药物的药物动力学是药物的宏观性质在吸收、 分布、代谢和排泄上的反映 基于性质的药物设计（PBDD）指的是针对药物或 药物候选物结构进行药动学性质设计与优化，以 实现药物或药物候选物的良好口服吸收、定向分 布、可控代谢、优化消除或降低毒副作用的目的。 性质是药物分子的宏观与微观结构的综合反映
有机体对药物的处置过程:药物动力学 口服制剂 崩解 肝肠循环 胃肠道 吸收(主动、被动) 药泵 血液循环 口个个个 结合 分布(主动、被动) 代谢 血浆蛋白 作用部 其他组织和器官 排泄 代谢)(分布 排泄物 代谢物
有机体对药物的处置过程：药物动力学
PK verSus PD Consider the following situations Appropriate transportation v Metabolism-activated pro-drugs Pharmacogenetics OOCH OLOCH3 N >P4502c19 HOOC Lack of efficacy Cl HS Cl White 2% clopidogre Black 4% Sales of $9B active metabolites Chinese 14% worldwide in 2010 SANOFI Platelet ADP receptor A Bristol-Myers squibb P2Y12 antagonist Together we can prevail
PK versus PD Pharmacogenetics P450 2C19 clopidogrel Platelet ADP receptor P2Y12 antagonist active metabolites Lack of efficacy White 2% Black 4% Sales of $9B Chinese 14% worldwide in 2010 Consider the following situations： Appropriate transportation Metabolism-activated pro-drugs
食物药物相互作用 ( Food-drug interactions Grapefruit-drug interactions 抑制CYP3A4,P-糖蛋白及 OATPs 至少与85种药物发生相互作用 benzodiazepines, ritonavir sertraline..) 需考虑食物-药物相互作用潜力的药物 CYP3A4底物 生物利用度低 Other food-drug interactions: alcohol, nicotine, caffeine
食物药物相互作用 （Food–drug interactions） Grapefruit–drug interactions • 抑制CYP3A4，P-糖蛋白及OATPs • 至少与85种药物发生相互作用 （benzodiazepines, ritonavir, sertraline…） 需考虑食物-药物相互作用潜力的药物： • CYP3A4底物 • 生物利用度低 Other food-drug interactions: alcohol, nicotine, caffeine, …
PK versus Safety Consider the following situations v Fast elimination v Rapid distribution to other non target tissues (Distribution) (Metabolism Accumulation) Morphine administration is In the United states and the associated with both analgesia and United Kingdom, paracetamol constipation toxicity is the most common The blood s ability to clot must be cause of acute liver failure carefully monitored while a person The grey syndrome has occurred takes warfarin in premature and other newborn infants receiving large doses of chloramphenicol
PK versus Safety Consider the following situations： Fast elimination Rapid distribution to other nontarget tissues (Distribution) • Morphine administration is associated with both analgesia and constipation • The blood's ability to clot must be carefully monitored while a person takes warfarin. （Metabolism & Accumulation） • In the United States and the United Kingdom, paracetamol toxicity is the most common cause of acute liver failure. • The grey syndrome has occurred in premature and other newborn infants receiving large doses of chloramphenicol