Albumin-Based Transport of Nonsteroidal Anti-Inflammatory Drugs in Mammalian Blood Plasma

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.