RT Journal Article
SR Electronic
T1 Canine albumin polymorphisms and their impact on drug plasma protein binding
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.087304
DO 10.1124/dmd.119.087304
A1 Ana Petra Costa
A1 Michael H Court
A1 Neal S Burke
A1 Zhaohui Zhu
A1 Katrina L Mealey
A1 Nicolas F Villarino
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/09/03/dmd.119.087304.abstract
AB Drug binding to plasma proteins is routinely determined during drug development. Albumin polymorphisms c.1075G>T (p.Ala359Ser) and c.1422A>T (p.Glu474Asp) were previously shown to alter plasma protein binding of a drug candidate (4-[1-[3-chloro-4-[n′-(2-methylphenyI)ureido]phenylacetyI]-(45)-fluoro-(2S)-pyrroIidine-2-yl]methoxybenzoic acid, D01-4582) in a colony of Beagles. Our study investigated the hypothesis that drug-protein binding in plasma from dogs with albumin H1 (reference) allele would be greater than in plasma from albumin H2 allele dogs (c.1075G>T and c.1422A>T) (n = 6 per group). Plasma protein binding extent of four drugs (D01-4582, celecoxib, mycophenolic acid, and meloxicam) was evaluated using ultracentrifugation or equilibrium dialysis. Free and total drug concentrations were analyzed by liquid chromatography-mass spectrometry. The albumin gene coding region was sequenced in 100 dogs to detect novel gene variants, and H1/H2 allele frequency determined in a large and varied population (n = 1446 from 61 breeds and mixed-breed dogs). For meloxicam, H1 allele plasma had statistically significant higher free drug fractions (P = 0.041) than H2 allele plasma. No significant difference was identified for plasma protein binding of D01-4582, celecoxib or mycophenolic acid. c.1075G>T and c.1422A>T were the most common SNPs in canine albumin, present concurrently in most study dogs and occasionally identified independently. In conclusion, albumin polymorphism c.1075G>T and c.1422A>T seems to affect the extent of plasma protein binding of meloxicam but not D01-4582, celecoxib, mycophenolic acid.SIGNIFICANCE STATEMENT These results suggest that c.1075G>T and c.1422A>T are frequent in the dog population and can influence the extent of plasma protein binding of some drugs. The impact of albumin polymorphisms on plasma drug disposition will depend on intrinsic total and/or free drug clearances. Albumin polymorphisms could result in inter-individual variability in drug disposition. Thus, albumin genotyping could improve interpretation of canine pharmacokinetic data generated during the drug development process for humans and dogs.