title: Interindividual pharmacokinetics variability of the alpha(4)beta(1) 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.
abstract: The interindividual pharmacokinetic variability of the alpha(4)beta(1) 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.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan. ito.takashi.uh@daiichisankyo.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sudo
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018076:DNA, Complementary / Q000235:genetics; D004285:Dogs; D005838:Genotype; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D010671:Phenylurea Compounds / Q000097:blood / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000235:genetics* / Q000378:metabolism
chemical_list: C516971:4-(1-(3-chloro-4-(N-(2-methylphenyl)ureido)phenylacetyl)-4-fluoropyrrolidine-2-yl)methoxybenzoic acid; D018076:DNA, Complementary; D039041:Integrin alpha4beta1; D010671:Phenylurea Compounds; D011759:Pyrrolidines; D012709:Serum Albumin