Barbato Francesco, di Martino Giuseppina, Grumetto Lucia, La Rotonda Maria Immacolata
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Via D. Montesano, 49 I-80131 Naples, Italy.
Eur J Pharm Sci. 2005 Jul-Aug;25(4-5):379-86. doi: 10.1016/j.ejps.2005.03.011.
The chromatographic capacity factors (k') of 10 beta-adrenoceptor antagonists ("beta-blockers") were measured on three different immobilized artificial membrane-phosphatidylcholine (IAM-PC) HPLC stationary phases, namely IAM-PC-MG, IAM-PC-DD2, and IAM-PC-DD. The two former phases are made of phosphatidylcholine as found in biomembranes and differ each other in end-capping of free propylamino residues whereas the latter is made of single-chain phosphatidylcholine analogues. On IAM-PC-DD2 we found that structurally unrelated neutral compounds give a single correlation between logk' values and the respective octanol/water partition coefficients (logP), as previously observed on IAM-PC-MG phase. This was not observed on the IAM-PC-DD phase. IAM chromatography was performed at a pH of the aqueous eluent (7.0) close to the physiological pH 7.4. Retention on all IAM phases showed a biphasic pattern, being proportional to logP(N) (lipophilicity of neutral forms) for more lipophilic congeners (logP(N)>1.90), and quite constant for the others. The comparison of beta-blocker retention with that of neutral compounds on IAM-PC-MG and IAM-PC-DD2 suggests that they can interact with phospholipids as strongly or more strongly than neutral isolipophilic compounds, despite their being more than 98% in their ionized form. Therefore, we hypothesize that electrostatic interactions play a pivotal role in the interactions between beta-blockers and membrane phospholipids.
在三种不同的固定化人工膜 - 磷脂酰胆碱（IAM - PC）高效液相色谱固定相上，即IAM - PC - MG、IAM - PC - DD2和IAM - PC - DD，测量了10种β - 肾上腺素能拮抗剂（“β - 阻滞剂”）的色谱容量因子（k'）。前两种固定相由生物膜中发现的磷脂酰胆碱制成，在游离丙基氨基残基的封端方面彼此不同，而后者由单链磷脂酰胆碱类似物制成。在IAM - PC - DD2上，我们发现结构不相关的中性化合物的logk'值与各自的正辛醇/水分配系数（logP）之间呈现单一相关性，这与之前在IAM - PC - MG固定相上观察到的情况相同。而在IAM - PC - DD固定相上未观察到这种情况。IAM色谱在水相洗脱液pH值为7.0（接近生理pH值7.4）的条件下进行。在所有IAM固定相上的保留呈现双相模式，对于亲脂性更强的同系物（logP(N)>1.90），保留与logP(N)（中性形式的亲脂性）成正比，而对于其他同系物则相当恒定。β - 阻滞剂在IAM - PC - MG和IAM - PC - DD2上的保留与中性化合物的比较表明，尽管它们98%以上处于离子化形式，但它们与磷脂的相互作用可能与中性等亲脂性化合物一样强或更强。因此，我们推测静电相互作用在β - 阻滞剂与膜磷脂之间的相互作用中起关键作用。
