Mechanism for Covalent Binding of MLN3126, an Oral Chemokine C-C Motif Receptor 9 Antagonist, to Serum Albumins
Autor: | Kimio Tohyama, Toshiyuki Takeuchi, Akio Morohashi, Satoru Asahi, Naohiro Narita, Takahiro Kondo, Yoshihiko Tagawa |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male Stereochemistry Chemical structure Serum albumin Pharmaceutical Science Administration Oral Pronase Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Receptors CCR Dogs Oral administration medicine Animals Humans Serum Albumin Pharmacology Sulfonamides Schiff base biology Albumin Antagonist Trypsin Rats 030104 developmental biology chemistry biology.protein medicine.drug Protein Binding |
Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 46(3) |
ISSN: | 1521-009X |
Popis: | 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 e-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. |
Databáze: | OpenAIRE |
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