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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Marked Strain Differences in the Pharmacokinetics of an ₄₁ Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Drug Metabolism and Physicochemistry Research Laboratory, R&D Division, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan (T.I., M.T., K.S.); and Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.S.)

Strain differences in pharmacokinetics of an ₄₁ integrin antagonist, 4-[1-[3-chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid (D01-4582), in Sprague-Dawley rat strains (SD rat and CD rat) and their mechanism were investigated. Total plasma clearances of D01-4582 were 31.5 and 5.23 ml/min/kg in SD and CD rats, respectively. From in vivo studies, hepatic uptake process was thought to be involved in the strain differences. Differences in the uptake of D01-4582 by isolated hepatocytes prepared from the both strains were not observed when hepatocytes were incubated with simple buffer, but marked differences were observed when hepatocytes were incubated with plasma. When the dissociation constants (K_d) for the plasma protein binding of D01-4582 were examined in six rat strains, each strain was classified into two groups: a high-K_d group, which included SD rats, Brown Norway rats, and Wistar rats; and a low-K_d group, which included CD rats, Lewis rats, and Eisai hyperbilirubinemic rats. Since all rat strains in the low-K_d group showed higher area under the concentration-time curve for D01-4582 than rats in the high-K_d group, it was considered that the strain differences in the pharmacokinetics of D01-4582 were due to differences in the binding affinity. Purified albumin also showed strain differences in K_d. The cDNA sequence of the albumin was analyzed, and 11 substitutions were observed. V238L and T293I were found only in the high-K_d group, suggesting that these amino acid changes reduced the binding affinity of albumin for D01-4582. In conclusion, the strain differences in D01-4582 pharmacokinetics were suggested to be caused by an alteration in K_d, associated with albumin genetic polymorphism.

Address correspondence to: Dr. Takashi Ito, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. E-mail: itoutpcb{at}daiichipharm.co.jp

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