TY - JOUR T1 - Mechanism for Covalent Binding of MLN3126, an Oral Chemokine C-C Motif Receptor 9 Antagonist, to Serum Albumins JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.078782 SP - dmd.117.078782 AU - Naohiro Narita AU - Akio Morohashi AU - Kimio Tohyama AU - Toshiyuki Takeuchi AU - Yoshihiko Tagawa AU - Takahiro Kondo AU - Satoru Asahi Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/12/21/dmd.117.078782.abstract N2 - N-{4-Chloro-2-[(1-oxidopyridin-4-yl)carbonyl]phenyl}-4-(propan-2-yloxy) benzenesulfonamide (MLN3126) is an orally available chemokine C-C motif receptor 9 selective antagonist. In non-clinical pharmacokinetic studies of MLN3126, non-extractable radioactivity was observed in plasma after oral administration of 14C-labeled MLN3126 ([14C]MLN3126) to Sprague-Dawley (SD) rats. In this study, the non-extractable radioactive component was digested with trypsin or a nonspecific protease, pronase, after chemical reduction to obtain drug-peptide adducts or drug-amino acid adducts. The chemical structure of these adducts were characterized by liquid chromatography/mass spectrometry. The results demonstrated that the major part of the non-extractable radioactivity was accounted for by covalent binding via the Schiff base formed specifically between the ε-amino group of lysine residue 199 in rat serum albumin and the carbonyl group of MLN3126. The t1/2 of the total radioactivity in plasma during and after 21 daily multiple oral administrations of [14C]MLN3126 to SD rats was approximately 5-fold shorter than the reported t1/2 of albumin in rats. The data indicated that the covalent binding was reversible under physiological conditions. The formation of the covalent binding was also confirmed in in vitro incubations with serum albumins from rats, humans, and dogs in the same manner, indicating that there are not qualitative interspecies differences in the formation of the Schiff base. ER -