The aim of the study was to use in silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug-transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (Papp), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a ΔGPB value -38.24 kcal/mol, darunavir a ΔGPB value -36.84 kcal/mol. The rank order of permeability of the compounds in vitro was tenofovir < darunavir < dapivirine. The Papp for tenofovir in Caco-2 cell monolayers was 0.10 ± 0.02 × 10-6 cm/s, ER = 1. For dapivirine, Papp was 32.2 ± 3.7 × 10-6 cm/s, but the ER = 1.3 was lower than anticipated based on the in silico findings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (Papp = 6.4 ± 0.9 × 10-6 cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silico modeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silico modeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that in silico modeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly different permeability, but was not interdependent.

译文

该研究的目的是使用计算机和体外技术来评估抗逆转录病毒药物的三重制剂 (替诺福韦,达罗纳韦和达比韦林) 是否与P-糖蛋白 (P-gp) 相互作用或表现出任何其他渗透性改变的药物-大肠粘膜中的药物相互作用。最初使用分子对接筛选与P-gp的潜在药物相互作用,然后进行分子动力学模拟,以更机械地分析已鉴定的药物-转运蛋白相互作用。在Caco-2细胞模型和结直肠组织中研究了替诺福韦,达鲁纳韦和达比韦林的转运,并评估了它们的表观渗透系数 (Papp),流出比 (ER) 和转运蛋白抑制剂的作用。在计算机中,达皮韦林和达卢纳韦对P-gp表现出很强的亲和力,具有相似的结合自由能; 达皮韦林表现出 Δ gpb值-38.24 kcal/mol,达卢纳韦a Δ gpb值-36.84 kcal/mol。化合物体外通透性的等级顺序为替诺福韦 <达瑞那韦 <达瑞韦林。替诺福韦在Caco-2细胞单层中的Papp为0.10 ± 0.02 × 10-6厘米/s,ER = 1。对于dapivirine,Papp为32.2 ± 3.7 × 10-6厘米/s,但ER = 1.3低于基于计算机研究结果的预期。替诺福韦和达比韦林的转运均不受P-gp抑制剂的影响。darunavir的吸收渗透率 (Papp = 6.4 ± 0.9 × 10-6厘米/s) 与ER = 6.3有关,维拉帕米将其降低至1.2。与作为单一药物施用相比,联合施用药物不会改变其渗透性。总之,在计算机模拟,细胞培养和基于组织的测定中,替诺福韦不与P-gp相互作用,渗透性差,与细胞旁转运机制一致。在计算机模拟中预测darunavir和dapivirine是P-gp底物,但只有darunavir在生物模型中显示出P-gp依赖性渗透性,这说明在计算机模拟中需要实验验证。当联合给药时,拟议的三联疗法抗逆转录病毒药物在大肠粘膜中的配置将取决于它们明显不同的渗透性,但不是相互依存的。

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