Bošković Jelena, Dobričić Vladimir, Savić Jelena, Rupar Jelena, Aleksić Mara, Marković Bojan, Čudina Olivera
Department of Pharmaceutical Chemistry, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Department of Physical Chemistry and Instrumental Methods, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Pharmaceuticals (Basel). 2024 Oct 5;17(10):1329. doi: 10.3390/ph17101329.
Evaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds , , , and , respectively) with dual COX-2 and 5-LOX inhibitory activity. Two in vitro methods (biopartitioning micellar chromatography (BMC) and PAMPA) were used to evaluate passive gastrointestinal absorption, while high-performance affinity chromatography (HPAC) and differential pulse voltammetry (DPV) were used to evaluate binding to human serum albumin (HSA). The introduction of N-hydroxyurea and hydroxamic acid groups into the structure of NSAIDs decreases both expected passive gastrointestinal absorption (BMC values were from 3.02 to 9.50, while for NSAIDs were from 5.29 to 13.36; PAMPA values were between 3.81 and 4.76, while for NSAIDs were ≤3.46) and HSA binding (HPAC values were from 2.03 to 9.54, while for NSAIDs were ≥11.03; DPV peak potential shifts were between 7 and 34, while for NSAIDs were ≥54). Structural modifications of all tested compounds that increase lipophilicity could be considered to enhance their passive gastrointestinal absorption. Considering lower expected HSA binding and higher lipophilicity of tested compounds compared to corresponding NSAIDs, it can be expected that the volume of distribution of compounds , , , and will be higher. Reduced HSA binding may also decrease interactions with other drugs in comparison to corresponding NSAIDs. All tested compounds showed significant microsomal instability (25.07-58.44% decrease in concentration) in comparison to indomethacin (14.47%) and diclofenac (20.99%).
药代动力学性质评估是药物研发早期的重要步骤。在本研究中，对五种新合成化合物的药代动力学性质进行了体外评估。这些化合物属于N - 羟基脲和异羟肟酸衍生物，是具有双重COX - 2和5 - LOX抑制活性的非甾体抗炎药吲哚美辛、氟比洛芬、双氯芬酸、布洛芬和萘普生的类似物（分别为化合物1、2、3、4和5）。使用两种体外方法（生物分配胶束色谱法（BMC）和平行人工膜渗透法（PAMPA））评估被动胃肠道吸收，同时使用高效亲和色谱法（HPAC）和差分脉冲伏安法（DPV）评估与人血清白蛋白（HSA）的结合。将N - 羟基脲和异羟肟酸基团引入非甾体抗炎药结构中，会降低预期的被动胃肠道吸收（BMC值为3.02至9.50，而非甾体抗炎药为5.29至13.36；PAMPA值在3.81至4.76之间，而非甾体抗炎药≤3.46）以及HSA结合（HPAC值为2.03至9.54，而非甾体抗炎药≥11.03；DPV峰电位偏移在7至34之间，而非甾体抗炎药≥54）。可以认为，所有测试化合物增加亲脂性的结构修饰可增强其被动胃肠道吸收。与相应的非甾体抗炎药相比，考虑到测试化合物预期的较低HSA结合和较高亲脂性，预计化合物1、2、3、4和5的分布容积会更高。与相应的非甾体抗炎药相比，降低的HSA结合也可能减少与其他药物的相互作用。与吲哚美辛（14.47%）和双氯芬酸（20.99%）相比，所有测试化合物均表现出显著的微粒体不稳定性（浓度降低25.07 - 58.44%）。
