Organic Anion Transporter 3 Interacts Selectively with Lipophilic β-Lactam Antibiotics
Organic Anion Transporter 3 Interacts Selectively with Lipophilic β-Lactam Antibiotics
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DOI：
10.1124/dmd.112.049569
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发表时间：
2013-04
影响因子：
3.9
通讯作者：
A. Wolman;M. Gionfriddo;Gregory A. Heindel;Paran Mukhija;S. Witkowski;A. Bommareddy;Adam L VanWert
中科院分区：
文献类型：
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作者：
A. Wolman;M. Gionfriddo;Gregory A. Heindel;Paran Mukhija;S. Witkowski;A. Bommareddy;Adam L VanWert
转运蛋白是体内外源性化学物质和内源性化学物质处置的主要决定因素。有机阴离子转运蛋白 3 (Oat3) 在肾脏和大脑中发挥作用，清除代谢废物、毒素和药物，从而转运多种化学物质。一些 β-内酰胺抗生素与 Oat3 相互作用，青霉素 G 在肾脏消除方面表现出对 Oat3 的强烈依赖性。然而，存在超过 80 种 β-内酰胺，其中许多尚未评估与 Oat3 的相互作用。此外，β-内酰胺继续获得美国食品和药物管理局的批准。这项研究确定了新的 β-内酰胺-Oat3 相互作用，提供了与 Oat1 的头对头比较，并表征了 Oat3 亲和力的物理化学决定因素。使用表达小鼠 Oat3 (mOat3) 和 Oat1 (mOat1) 以及人 OAT3 (hOAT3) 的细胞来测试抑制剂，并使用高效液相色谱 (HPLC) 来测量转运。在测试的 26 种 β-内酰胺中，12 种是明确的 Oat3 抑制剂，14 种表现出较差的相互作用。抑制剂对 mOat3 和 hOAT3 表现出几乎相同的效力排序。 Oat1 与大多数 β-内酰胺的相互作用较差。大多数Oat3抑制剂都是底物，抑制剂和非抑制剂之间存在明显的理化差异。也就是说，抑制剂的氢键供体减少了近 40% (P < 0.001)，总极性表面积更低 (P < 0.05)，亲脂性更高（抑制剂的 LogP，+1.41；非抑制剂，-1.54；P < 0.001）。药效团作图揭示了非抑制剂中与疏水部分相邻的禁止性氢键供体基团，该疏水部分对于与 Oat3 的结合非常重要。这些发现表明 Oat3 更容易识别亲脂性 β-内酰胺。此外，这项研究对于设计 β-内酰胺以避免通过 Oat3 进行肾脏蓄积或脑外流具有潜在意义。
Transporters are major determinants of the disposition of xenobiotics and endogenous chemicals in the body. Organic anion transporter 3 (Oat3) functions in the kidney and brain to remove metabolic waste, toxins, and drugs, and thus transports diverse chemicals. Some β-lactam antibiotics interact with Oat3, and penicillin G exhibits a strong dependence on Oat3 for renal elimination. However, over 80 β-lactams exist, and many have not been assessed for an interaction with Oat3. Moreover, β-lactams continue to receive U.S. Food and Drug Administration approval. This study identified new β-lactam–Oat3 interactions, provided a head-to-head comparison with Oat1, and characterized the physicochemical determinants of affinity for Oat3. Cells expressing mouse Oat3 (mOat3) and Oat1 (mOat1), and human OAT3 (hOAT3) were used to test inhibitors, and high-performance liquid chromatography (HPLC) was used to measure transport. Of 26 β-lactams tested, 12 were clear inhibitors of Oat3, and 14 exhibited poor interactions. Inhibitors exhibited a nearly identical rank-order of potency against mOat3 and hOAT3. Oat1 demonstrated a poor interaction with most β-lactams. The majority of Oat3 inhibitors were substrates, and there were clear physicochemical differences between inhibitors and noninhibitors. That is, inhibitors had nearly 40% fewer hydrogen bond donors (P < 0.001), a lower total polar surface area (P < 0.05), and greater lipophilicity (LogP of inhibitors, +1.41; noninhibitors, −1.54; P < 0.001). Pharmacophore mapping revealed a prohibitive hydrogen bond donor group in noninhibitors adjacent to a hydrophobic moiety that was important for binding to Oat3. These findings indicate that Oat3 recognizes lipophilic β-lactams more readily. Moreover, this study has potential implications for designing β-lactams to avoid renal accumulation or brain efflux via Oat3.