2013首届北方药学研究生论坛-曾苏-ADME在药物研发中及作用--从成药性评价到新药转化研究.ppt

LLC-PK1/BCRP细胞 +抑制剂 3. CNS BBB P450 UGT Initially, CYP1A2, CYP2B6, and CYP3A should be evaluated in vitro Drug is not an inducer of CYP3A4 then it can be concluded that the test drug is also not an inducer of CYP2C8, CYP2C9, or CYP2C19 Overcoming a Limited Absorption Window Stomach Small Intestine Colon 2 to 4 hours 1 to 6 hours 8 to 18 hours High Capacity Transporter Increased bioavailability Greater dose proportionality Lower inter-patient variability Reduced dosing frequency (sustained release) Modify the drug for recognition by high capacity transporters located throughout the intestine: MCT-1和SMVT的底物 XP13512 (IR) vs. Neurontin: Concentrations of Gabapentin in Blood Effect of Dose on Concs. of Gabapentin in Blood After Oral Administr. of Neurontin or XP13512 to Healthy Adults All AEs reported for XP13512 were mild and similar to those reported for Neurontin XP13512: Dose Proportionality of AUC Effect of Dose on AUC of Gabapentin in Blood After Oral Administration of XP13512 or Neurontin XP13512 produced dose-proportional exposure Neurontin exposure showed saturation R2 = 0.994 XP13512: High Bioavailability as Gabapentin Effect of Dose on Bioavailability as Gabapentin After Oral Administration of XP13512 or Neurontin? to Healthy Volunteers Neurontin absorption was saturated No saturation of XP13512 absorption or conversion to gabapentin XP13512: Very Low Exposure to Prodrug Concs of Gabapentin and Intact XP13512 in Blood After Oral Administ of XP13512 to Healthy Volunteers at 2800 mg Gabapentin Cmax was 50-fold higher than prodrug Cmax Gabapentin AUC was 280-fold higher than prodrug AUC 3. 基于代谢物的新药发现和药物设计 研究药物在体内外的代谢物 设计生物转化激活的前体药物 发现一些活性代谢物比母体药物更安全有效或再经过结构修饰发现新药 新药发现和药物设计的一种重要来源 Phenacetin, 1887 (nephrotoxic, methemoglobinemia) Recognized as active metabolite of phenacetin in 1948; popular in US since 1955 磺胺 还原 CYP3A4 Terfenadine (Seldane) Fexofenadine (Allegra) CYP3A4,2C19 Diazepam Oxazepam 4. 药物代谢性质用于制剂设计 抗哮喘药异丙肾上腺素 在肠道和肝中代谢而迅速失活，口服给药方式无法使