Structural Basis of Non-Steroidal Anti-Inflammatory Drug (NSAID) Transport by Serum Albumin

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used medicines in the world and are often co-administered with other drugs. More than 70 million people in the USA take NSAIDs at least three times per week for more than three months, and about 70% of people who take any prescription drug use more than one drug at the same time. NSAIDs are transported in the bloodstream by plasma proteins, mainly by serum albumin (SA), which is the main carrier of small molecules in the blood. More than 900 FDA-approved drugs are known to bind to plasma proteins, primarily albumin, but complexes of SA with only 31 FDA-approved drugs have been structurally studied. We report the first crystal structures of equine serum albumin in complexes with four NSAIDs (ibuprofen, ketoprofen, etodolac, nabumetone) and the major metabolite of nabumetone (6-methoxy-2-naphthylacetic acid). Prior to our studies, ibuprofen and ketoprofen complexes with other SAs (human and bovine SA, respectively) were crystallized, and we discuss similarities and differences in their binding to SAs from different species. Our analysis of all known albumin drug-binding sites shows that various drugs share common binding sites, which can lead to drug-drug displacement or other unwanted and dangerous effects during drug co-administration in patients. Also, non-enzymatic glycosylation (glycation) and other modifications may affect a drug's binding to albumin and its free blood concentration, which is especially important for drugs with a narrow therapeutic index. Information about the location of NSAID binding sites contributes to a better understanding of the drug-drug displacement phenomena and the effect of metabolic disorders on drug transport. Our results suggest that altered drug doses may be needed to achieve desired therapeutic effects and avoid toxicity in relevant cases.