Interindividual Pharmacokinetics Variability of the α4β1 Integrin Antagonist, 4-[1-[3-Chloro-4-[N′-(2-methylphenyl) ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl] methoxybenzoic Acid (D01-4582), in Beagles Is Associated with Albumin Genetic Polymorphisms

Add time:08/21/2019    Source:sciencedirect.com

ABSTRACTThe interindividual pharmacokinetic variability of the α4β1 integrin antagonist 4-[1-[3-Chloro-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid (D01-4582) was observed in beagles. The involvement of albumin genetic polymorphism in this variability was investigated. The albumin genotype was analyzed by sequencing the albumin gene from liver and blood samples. The plasma protein binding of D01-4582 was analyzed using an ultracentrifuge method. The results of the sequencing analysis of albumin cDNA revealed two single nucleotide polymorphisms, G1075T and A1422T, leading to amino acid changes of Ala335Ser, and Glu450Asp, respectively. These mutations show complete linkage. The prevalence of the mutant allele in a population of 47 dogs was 40%. The unbound fractions of D01-4582 in plasma decreased in the order of homozygous, heterozygous, and wild-type beagles. The equilibrium dissociation constants in the plasma from homozygous beagles were approximately sixfold greater than those for wild-type beagles. Prospective pharmacokinetic study using genotyped beagles demonstrated that the clearance was related to albumin genotype. The variability in clearance was well explained by changes in the unbound fractions. These results suggest that the interindividual variability in the canine pharmacokinetics of D01-4582 is related to an alteration in the binding affinity which is associated with albumin genetic polymorphisms.

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