RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 204
OP 213
DO 10.1124/dmd.117.078782
VO 46
IS 3
A1 Naohiro Narita
A1 Akio Morohashi
A1 Kimio Tohyama
A1 Toshiyuki Takeuchi
A1 Yoshihiko Tagawa
A1 Takahiro Kondo
A1 Satoru Asahi
YR 2018
UL http://dmd.aspetjournals.org/content/46/3/204.abstract
AB 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 nonclinical pharmacokinetic studies of MLN3126, nonextractable radioactivity was observed in plasma after oral administration of 14C-labeled MLN3126 ([14C]MLN3126) to Sprague-Dawley (SD) rats. In this study, the nonextractable 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 was characterized by liquid chromatography/mass spectrometry. The results demonstrated that the major part of the nonextractable 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 half-life (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 physiologic 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 no qualitative interspecies differences in the formation of the Schiff base.