Divalent Metals and pH Alter Raltegravir Disposition In Vitro
Divalent Metals and pH Alter Raltegravir Disposition In Vitro
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DOI：
10.1128/aac.06407-11
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Owen, Andrew
中科院分区：
文献类型：
--
作者：
Moss, Darren M.;Siccardi, Marco;Owen, Andrew
雷特格韦在患者中显示出显著的药代动力学变异性，胃肠道pH值和二价金属结合是潜在因素。我们研究了雷特格韦的溶解度、亲脂性、pk（a）和体外渗透性，以阐明与奥美拉唑、抗酸剂和食物的已知相互作用，所有这些都会增加胃pH值。在pH 1至8下测定雷特格韦的溶解度。采用辛醇-水分配法测定雷特格韦的亲脂性。采用UV光谱法测定雷特格韦pk（a）。使用Caco-2单层测定pH值、金属盐和奥美拉唑对雷特格韦细胞渗透性的影响。细胞蓄积研究用于确定pH和ABCB 1转运之间的相互作用对雷特格韦蓄积的影响。采用液相色谱-串联质谱法（LC-MS/MS）或闪烁计数法分析样品。10 mM的雷特格韦在pH 6.6及以下部分不溶。雷特格韦亲脂性具有pH依赖性，并且随着pH从5增加至9而降低。雷特格韦的pk（a）为6.7。雷特格韦细胞渗透性受到细胞外pH变化的严重影响，其中当顶端pH从5增加到8.5时，顶端到基底外侧的渗透性降低9倍（P < 0.05）。在镁和钙的存在下，雷特格韦的细胞渗透性也降低。奥美拉唑不会改变雷特格韦的细胞渗透性。通过抑制ABCB 1和将细胞外pH从pH 8降低至5，可独立增加雷特格韦的细胞蓄积。胃肠道pH值和多价金属可能会改变雷特格韦的药代动力学特性，这些数据为患者中雷特格韦暴露的变异性提供了解释。现在，对不影响胃pH值的含二价金属的产品（如多维生素）如何改变患者中雷特格韦的药代动力学进行评价是合理的。
Raltegravir shows marked pharmacokinetic variability in patients, with gastrointestinal pH and divalent-metal binding being potential factors. We investigated raltegravir solubility, lipophilicity, pk(a), and permeativity in vitro to elucidate known interactions with omeprazole, antacids, and food, all of which increase gastric pH. Solubility of raltegravir was determined at pH 1 to 8. Lipophilicity of raltegravir was determined using octanol-water partition. Raltegravir pk(a) was determined using UV spectroscopy. The effects of pH, metal salts, and omeprazole on the cellular permeativity of raltegravir were determined using Caco-2 monolayers. Cellular accumulation studies were used to determine the effect of interplay between pH and ABCB1 transport on raltegravir accumulation. Samples were analyzed using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) or scintillation counting. Raltegravir at 10 mM was partly insoluble at pH 6.6 and below. Raltegravir lipophilicity was pH dependent and was reduced as pH was increased from 5 to 9. The pk(a) of raltegravir was 6.7. Raltegravir cellular permeativity was heavily influenced by changes in extracellular pH, where apical-to-basolateral permeativity was reduced 9-fold (P < 0.05) when apical pH was increased from 5 to 8.5. Raltegravir cellular permeativity was also reduced in the presence of magnesium and calcium. Omeprazole did not alter raltegravir cellular permeativity. Cellular accumulation of raltegravir was increased independently by inhibiting ABCB1 and by lowering extracellular pH from pH 8 to 5. Gastrointestinal pH and polyvalent metals can potentially alter the pharmacokinetic properties of raltegravir, and these data provide an explanation for the variability in raltegravir exposure in patients. The evaluation of how divalent-metal-containing products, such as multivitamins, that do not affect gastric pH alter raltegravir pharmacokinetics in patients is now justified.