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Albumin-Based Transport of Nonsteroidal Anti-Inflammatory Drugs in Mammalian Blood Plasma.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-29 , DOI: 10.1021/acs.jmedchem.0c00225 Mateusz P Czub 1, 2 , Katarzyna B Handing 1 , Barat S Venkataramany 1 , David R Cooper 1, 2 , Ivan G Shabalin 1, 2 , Wladek Minor 1, 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-29 , DOI: 10.1021/acs.jmedchem.0c00225 Mateusz P Czub 1, 2 , Katarzyna B Handing 1 , Barat S Venkataramany 1 , David R Cooper 1, 2 , Ivan G Shabalin 1, 2 , Wladek Minor 1, 2
Affiliation
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Every day, hundreds of millions of people worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs), often in conjunction with multiple other medications. In the bloodstream, NSAIDs are mostly bound to serum albumin (SA). We report the crystal structures of equine serum albumin complexed with four NSAIDs (ibuprofen, ketoprofen, etodolac, and nabumetone) and the active metabolite of nabumetone (6-methoxy-2-naphthylacetic acid, 6-MNA). These compounds bind to seven drug-binding sites on SA. These sites are generally well-conserved between equine and human SAs, but ibuprofen binds to both SAs in two drug-binding sites, only one of which is common. We also compare the binding of ketoprofen by equine SA to binding of it by bovine and leporine SAs. Our comparative analysis of known SA complexes with FDA-approved drugs clearly shows that multiple medications compete for the same binding sites, indicating possibilities for undesirable physiological effects caused by drug–drug displacement or competition with common metabolites. We discuss the consequences of NSAID binding to SA in a broader scientific and medical context, particularly regarding achieving desired therapeutic effects based on an individual’s drug regimen.
中文翻译：
基于白蛋白的哺乳动物血浆中非甾体抗炎药的运输。
每天，全球有成千上万人服用非甾体类抗炎药（NSAID），通常与多种其他药物联用。在血流中，NSAID主要与血清白蛋白（SA）结合。我们报告了马血清白蛋白与四个NSAIDs（布洛芬，酮洛芬，依托度酸和萘丁美酮）和萘丁美酮的活性代谢物（6-甲氧基-2-萘乙酸，6-MNA）复合的晶体结构。这些化合物与SA上的七个药物结合位点结合。这些位点在马和人的SA之间通常保持良好的保守性，但布洛芬在两个药物结合位点与两个SA结合，只有一个是常见的。我们还比较了马SA对酮洛芬的结合与牛SA和Leporine SA对其的结合。我们对已知SA配合物与FDA批准药物的比较分析清楚地表明，多种药物竞争相同的结合位点，这表明由药物-药物置换或与常见代谢物竞争引起的不良生理效应的可能性。我们将在更广泛的科学和医学背景下讨论NSAID与SA结合的后果，尤其是关于基于个体药物治疗方案实现所需治疗效果的问题。
更新日期：2020-07-09
中文翻译：
基于白蛋白的哺乳动物血浆中非甾体抗炎药的运输。
每天，全球有成千上万人服用非甾体类抗炎药（NSAID），通常与多种其他药物联用。在血流中，NSAID主要与血清白蛋白（SA）结合。我们报告了马血清白蛋白与四个NSAIDs（布洛芬，酮洛芬，依托度酸和萘丁美酮）和萘丁美酮的活性代谢物（6-甲氧基-2-萘乙酸，6-MNA）复合的晶体结构。这些化合物与SA上的七个药物结合位点结合。这些位点在马和人的SA之间通常保持良好的保守性，但布洛芬在两个药物结合位点与两个SA结合，只有一个是常见的。我们还比较了马SA对酮洛芬的结合与牛SA和Leporine SA对其的结合。我们对已知SA配合物与FDA批准药物的比较分析清楚地表明，多种药物竞争相同的结合位点，这表明由药物-药物置换或与常见代谢物竞争引起的不良生理效应的可能性。我们将在更广泛的科学和医学背景下讨论NSAID与SA结合的后果，尤其是关于基于个体药物治疗方案实现所需治疗效果的问题。
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