"Drug binding to mammalian serum albumins"

Serum albumin (SA) is the most abundant protein in mammalian blood plasma. SA is primarily responsible for the transport of drugs, hormones, fatty acids, metals, and various other metabolites in the blood. More than 900 FDA-approved drugs are known to bind to plasma proteins, mainly albumin, but prior to this study complexes of SA with only 29 FDA-approved drugs have been structurally characterized. In this thesis, I present several structures of human serum albumin (complexes with ketoprofen, JMS-053, myristic acid) and equine serum albumin (complexes with ibuprofen, ketoprofen, etodolac, nabumetone, 6-MNA, testosterone, progesterone, dexamethasone, hydrocortisone, warfarin, tolbutamide, haloperidol, ampicillin, GHK(Cu), and glucose). I also present the binding constant of testosterone to equine and human albumins determined by two different methods (tryptophan fluorescence quenching and ultrafast affinity extraction). Previously, ibuprofen, warfarin, and ketoprofen complexes with other SAs were crystallized, and I discuss similarities and differences in their binding to SAs from different species. The 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. To better describe the location of drug-binding sites in albumin, I distinguish ten drug sites and propose a novel nomenclature based on the previously characterized sites. I also discuss the effect of non-enzymatic glycosylation (glycation) of albumin and drug competition with fatty acids on 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 drug-binding sites contributes to a better understanding of the drug-drug displacement phenomena and the effect of metabolic disorders on drug transport. The results suggest that in some cases, physicians should consider altered drug doses that are needed to achieve desired therapeutic effects and avoid toxicity in relevant groups of patients.