Mason R P, Moisey D M, Shajenko L
Department of Radiology, University of Connecticut Health Center, Farmington 06030.
Mol Pharmacol. 1992 Feb;41(2):315-21.
X-ray diffraction and equilibrium binding techniques were used to study the effect of cholesterol on membrane binding of the charged 1,4-dihydropyridine (DHP) Ca2+ channel antagonist amlodipine and uncharged isradipine, nimodipine, and nitrendipine. Increases in membrane cholesterol content resulted in a marked decrease in DHP binding to cardiac phospholipid membranes, as expressed by the equilibrium partition coefficient (Kp[mem]). Between a 0:1 and 0.3:1 cholesterol to phospholipid mole ratio, the Kp(mem) values for isradipine, nimodipine, and nitrendipine decreased by greater than 50%, whereas that for amlodipine decreased by only 10%. Electron density profiles calculated from the X-ray diffraction data showed that the time-averaged locations for the DHPs and cholesterol in the membrane overlap, leading to the conclusion that the addition of cholesterol alters the lipid bilayer hydrocarbon core structure in a manner that makes drug partitioning into the membrane less energetically favorable. These data support the idea that drug interactions with the anisotropic membrane environment are complex and may be greatly influenced by cholesterol composition. This effect of cholesterol was also observed for phenylalkylamine (verapamil) and benzothiazepine (diltiazem) Ca2+ channel blockers. The DHP amlodipine had the highest membrane partition coefficient (Kp[mem] greater than 10(4) and the slowest rate of dissociation and was affected least by membrane cholesterol content. The combination of electrostatic and hydrophobic bonding between amlodipine and membrane phospholipid may explain the high affinity of this drug for the membrane bilayer with normal and elevated cholesterol. The results of this study show that cholesterol content differentially affects the membrane-binding properties of the charged DHP amlodipine, compared with other Ca2+ channel blockers. These data help explain the biological distribution of these drugs and the distinct pharmacokinetics of amlodipine versus other Ca2+ channel blockers.
采用X射线衍射和平衡结合技术，研究胆固醇对带电荷的1,4 - 二氢吡啶（DHP）钙通道拮抗剂氨氯地平以及不带电荷的伊拉地平、尼莫地平和尼群地平膜结合的影响。膜胆固醇含量增加导致DHP与心脏磷脂膜的结合显著减少，这由平衡分配系数（Kp[mem]）表示。在胆固醇与磷脂摩尔比从0:1增加到0.3:1的过程中，伊拉地平、尼莫地平和尼群地平的Kp(mem)值下降超过50%，而氨氯地平的Kp(mem)值仅下降10%。根据X射线衍射数据计算出的电子密度分布图显示，膜中DHP和胆固醇的时间平均位置重叠，由此得出结论：添加胆固醇会改变脂质双分子层烃核结构，使得药物分配到膜中的能量优势降低。这些数据支持了药物与各向异性膜环境的相互作用很复杂且可能受胆固醇组成极大影响这一观点。对于苯烷基胺（维拉帕米）和苯并硫氮䓬（地尔硫䓬）钙通道阻滞剂，也观察到了胆固醇的这种作用。DHP氨氯地平具有最高的膜分配系数（Kp[mem]大于10(4)）和最慢的解离速率，且受膜胆固醇含量的影响最小。氨氯地平和膜磷脂之间的静电和疏水键结合可能解释了该药物对正常和高胆固醇水平的膜双分子层具有高亲和力。本研究结果表明，与其他钙通道阻滞剂相比，胆固醇含量对带电荷的DHP氨氯地平的膜结合特性有不同影响。这些数据有助于解释这些药物的生物分布以及氨氯地平与其他钙通道阻滞剂不同的药代动力学。
