Change of drug binding ability of plasma lipoproteins due to oxidative modification

疏水性药物和碱性药物与血浆脂蛋白结合，对药物的处置和药效学有重要影响。低密度脂蛋白（LDL）在体内会发生氧化。这种氧化修饰可能影响药物结合能力，导致药代动力学性质的改变。LDL的某些组分如载脂蛋白是手性化合物。因此，手性药物与LDL的结合可能是对映选择性的。本研究采用高效前沿分析/毛细管电泳（HPFA/CE）方法，对LDL氧化对LDL与手性药物结合的影响进行了定量和对映选择性研究。结果表明：1）LDL的氧化修饰增强了模型药物维拉帕米、尼伐地平和氟伐他汀（降血脂药）的结合。LDL氧化2小时后，氟伐他汀的nK值增加2倍。2）模型药物与氧化LDL的结合是非特异性的，呈分区样结合。无论总药物浓度如何，结合药物分数都是恒定的。3）为了研究LDL脂质组分的氧化贡献，制备了几种不同酰基链结构或不同净电荷的模型脂质体，并考察了它们与模型碱性药物维拉帕米和普萘洛尔的结合特性。结果表明，LDL氧化过程中正净电荷的减少在药物结合亲和力的增强中起着最有效的作用。酰基链结构的变化不如净电荷的变化有效。

Hydrophobic drugs and basic drugs are bound to plasma lipoproteins, which gives significant effect upon drug disposition and pharmacodynamics. Low-density lipoprotein (LDL) suffers from in vivo oxidation. This oxidative modification may affect the drug binding ability, resulting in the change in the pharmacokinetic property. Some components of LDL such as apolipoproteins are chiral compounds. Therefore, binding of a chiral drug to LDL may be enantioselective. In this study, the effect of LDL oxidationt upon the binding between LDL and chiral drugs were investigated quantitatively and enantioselectively by using our original method, high-performance frontal analysis/capillary electrophoresis (HPFA/CE). The following results were found.1) The oxidative modification of LDL enhanced the binding of model drugs such as verapamil, nilvadipine and fluvastatin (antihyperlipidemia). The nK value of fluvastatin was increased by two-fold after 2-hr LDL oxidation.2) The binding of model drugs to oxidized LDL is non-specific and partition like binding. The bound drug fraction is constant regardless of the total drug-concentration. No enantioselectivity was found in the drug oxidized LDL binding.3) In order to estimate the contribution of oxidation of LDL lipid components, several model liposomes containing different acyl-chain structure or different net charge were prepared, and their binding property with model basic drugs (verapamil and propranolol) was investigated. It was found that the decrease of positive net charge during LDL oxidation plays the most effective role in the enhancement of drug binding affinity. The change in acyl-chain structure is less effective than the change in the net charge.