Krämer S D, Jakits-Deiser C, Wunderli-Allenspach H
Department of Pharmacy, ETH Zürich, Switzerland.
Pharm Res. 1997 Jun;14(6):827-32. doi: 10.1023/a:1012175111401.
The influence of oleic acid (OA) and phosphatidylethanolamine (PhE) as membrane constituents on the partition behavior of (RS)-[3H]propranolol between unilamellar liposomes and buffer was studied as a function of pH.
Partition studies were performed by means of equilibrium dialysis at 37 degrees C over a broad pH range at a molar propranolol to lipid ratio in the membrane of 10(-6).
As compared to the standard phosphatidylcholine (PhC)-liposome/buffer partition system PhE and OA have an enhancing effect on the apparent partition coefficient (D) of (RS)-[3H]propranolol between pH 6 and 11. Data analysis with Henderson-Hasselbalch equations revealed that the neutral propranolol has a higher affinity to membranes containing net neutral charged PhE than to pure PhC-liposomes. Net negatively charged PhE seems to have no significant influence on the partitioning. Deprotonated OA caused an increase in the true partition coefficient (P) of the protonated propranolol. Neutral OA showed no influence on the partitioning. From the fit D vs pH curves and from zeta potential measurements of the liposomes the intrinsic pKa values of the membranous lipids were calculated as 7.5 to 7.8 for OA and 9.7 to 9.8 for PhE.
Since the pKa of membranous OA is close to the physiological pH and D depends on the ionisation state of OA, small pH changes around the physiological pH may cause large differences in drug-lipid membrane interactions.
研究油酸（OA）和磷脂酰乙醇胺（PhE）作为膜成分对（RS）-[3H]普萘洛尔在单层脂质体与缓冲液之间分配行为的影响，并考察其与pH的关系。
通过平衡透析法在37℃下，在较宽的pH范围内，以膜中普萘洛尔与脂质的摩尔比为10⁻⁶进行分配研究。
与标准磷脂酰胆碱（PhC）-脂质体/缓冲液分配系统相比，在pH 6至11之间，PhE和OA对（RS）-[3H]普萘洛尔的表观分配系数（D）有增强作用。用亨德森-哈塞尔巴尔赫方程进行数据分析表明，中性普萘洛尔对含有净中性电荷的PhE的膜的亲和力高于对纯PhC-脂质体的亲和力。净带负电荷的PhE似乎对分配没有显著影响。去质子化的OA使质子化普萘洛尔的真实分配系数（P）增加。中性OA对分配无影响。根据拟合的D对pH曲线以及脂质体的ζ电位测量值，计算出膜脂质的固有pKa值，OA为7.5至7.8，PhE为9.7至9.8。
由于膜OA的pKa接近生理pH，且D取决于OA的电离状态，因此在生理pH附近的小pH变化可能会导致药物-脂质膜相互作用产生很大差异。
