胆结合结构多样化的电离药物分子
Mayu Konishi1, Kiyohiko Sugano1
1Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
ADMET & DMPK
|August 11, 2025
概括
胆细胞未结合的部分是预测食物对药物吸收的影响的关键. 阴离子药物表现出微不足道的结合,而阴离子药物可以具有显著的结合,影响生理学基础的生物制药建模 (PBBM).
科学领域:
- 药理动力学和药物新陈代谢
- 生物制药建模 生物制药建模
- 物理化学 物理化学
背景情况:
- 基于生理学的生物制药建模 (PBBM) 在预测食物对口服药物吸收的影响方面面临挑战.
- 胆髓未结合分数 (f_u) 对于具有高溶解性的药物具有负面食物影响至关重要.
- 准确计算 PBBM 的 pH-f_u 概况,需要对有离子和无离子药物物种的胆分区系数 (K_bm,z).
研究的目的:
- 调查和建立一种一般规则,以确定化和非化药物物种 (K_bm,z≠0/K_bm,0) 之间的胆髓分离系数的比率.
- 了解药物电离状态对胆细胞分裂的影响.
- 提高 PBBM 在预测食品影响方面的准确性.
主要方法:
- 动态透析被用来测量各种弱酸,弱和zwitterionic药物的pH-f_u概况,其pH范围为pKa ± 2.
- 用特定度的塔罗霍尔酸 (TC) 和蛋莱西丁制备了胆囊.
- 胆分区系数 (K_bm,z) 由实验确定的pH-f_u配置文件计算出来.
主要成果:
- 对于所有单价弱酸,K_bm,-1/K_bm,0的比率是可以忽略不计的 (≤0.03).
- 对于单价弱基,K_bm+1/K_bm,0的差异很大 (0.24~2.6),对于双价弱基,K_bm+2/K_bm,0的差异约为0.3.
- 对于zwiterionic药物,K_bm,-1/K_bm,±0在1.1到2.3之间,K_bm+,1/K_bm,±0在3.9到20之间. K_bm,0 显示与八醇/水分区系数 (P_oct) 的中等相关性.
结论:
- 胆细胞的结合在阳离子药物物种中是最小的,但在阴离子物种中可以很大.
- 不能为K_bm+1/K_bm,0建立一个通用规则,在某些情况下,值超过1,表明潜在的有吸引力的静电相互作用.
- 这些发现对于改进 PBBM 和改善对药物吸收食物影响的预测至关重要.
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