季铵类药物的离子对分配：不同亲脂性、大小和柔韧性的抗衡离子的影响。

Ion-pair partition of quarternary ammonium drugs: the influence of counter ions of different lipophilicity, size, and flexibility.

作者信息

Takács-Novák K, Szász G

机构信息

Institute of Pharmaceutical Chemistry, Semmelweiss University of Medicine, Budapest, Hungary.

出版信息

Pharm Res. 1999 Oct;16(10):1633-8. doi: 10.1023/a:1018977225919.

DOI:10.1023/a:1018977225919

PMID:10554109

Abstract

PURPOSE

The ion-pair partition of quaternary ammonium (QA) pharmacons with organic counter ions of different lipophilicity, size, shape and flexibility was studied to elucidate relationships between ion-pair formation and chemical structure.

METHODS

The apparent partition coefficient (P') of 4 QAs was measured in octanol/pH 7.4 phosphate buffer system by the shake-flask method as a function of molar excess of ten counter ions (Y), namely: mesylate (MES), acetate (AC), pyruvate (PYRU), nicotinate (NIC), hydrogenfumarate (HFUM), hydrogenmaleate (HMAL), p-toluenesulfonate (PTS), caproate (CPR), deoxycholate (DOC) and prostaglandin E1 anion (PGE1).

RESULTS

Based on 118 of highly precise logP' values (SD< 0.05), the intrinsic lipophilicity (without external counter ions) and the ion-pair partition of QAs (with different counter ions) were characterized. Linear correlation was found between the logP' of ion-pairs and the size of the counter ions described by the solvent accessible surface area (SASA). The lipophilicity increasing effect of the counter ions were quantified and the following order was established: DOC approximate to PGE1 >> CPR approximate to PTS >> NIC approximate to HMAL >> PYRU approximate to AC approximate to MES approximate to HFUM. Analyzing the lipophilicity/molar ratio (QA:Y) profile, the differences in the ion-pair formation were shown and attributed to the differences in the flexibility/rigidity and size both of QA and Y.

CONCLUSIONS

Since the largest (in average, 300 X) lipophilicity enhancement was found by the influence of DOC and PGE1 and considerable (on average 40 X) increase was observed by CPR and PTS, it was concluded that bile acids and prostaglandin anions may play a significant role in the ion-pair transport of quaternary ammonium drugs and caproic acid and p-toluenesulfonic acid may be useful salt forming agents to improve the pharmacokinetics of hydrophilic drugs.

摘要

目的

研究具有不同亲脂性、大小、形状和柔韧性的有机抗衡离子的季铵（QA）药物的离子对分配，以阐明离子对形成与化学结构之间的关系。

方法

采用摇瓶法在正辛醇/pH 7.4磷酸盐缓冲体系中测定4种QA的表观分配系数（P'），该系数是十种抗衡离子（Y）摩尔过量的函数，这十种抗衡离子分别为：甲磺酸盐（MES）、乙酸盐（AC）、丙酮酸盐（PYRU）、烟酸盐（NIC）、富马酸盐（HFUM）、马来酸盐（HMAL）、对甲苯磺酸盐（PTS）、己酸盐（CPR）、脱氧胆酸盐（DOC）和前列腺素E1阴离子（PGE1）。

结果

基于118个高精度的logP'值（标准差<0.05），对QA的固有亲脂性（无外部抗衡离子）和离子对分配（有不同抗衡离子）进行了表征。发现离子对的logP'与通过溶剂可及表面积（SASA）描述的抗衡离子大小之间存在线性相关性。对抗衡离子的亲脂性增强作用进行了量化，并确定了以下顺序：DOC近似于PGE1 >> CPR近似于PTS >> NIC近似于HMAL >> PYRU近似于AC近似于MES近似于HFUM。通过分析亲脂性/摩尔比（QA:Y）曲线，显示了离子对形成的差异，并归因于QA和Y在柔韧性/刚性和大小方面的差异。