title: Alpha-amylase inhibitor, CS-1036 binds to serum amylase in a concentration-dependent and saturable manner.
abstract: (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036), which is an α-amylase inhibitor, exhibited biphasic and sustained elimination with a long t1/2 (18.4-30.0 hours) in rats and monkeys, but exhibited a short t1/2 (3.7-7.9 hours) in humans. To clarify the species differences in the t1/2, the plasma protein binding of CS-1036 was evaluated by ultrafiltration. A concentration-dependent and saturable plasma protein binding of CS-1036 was observed in rats and monkeys with the dissociation rate constant (KD) of 8.95 and 27.2 nM, and maximal binding capacity (Bmax) of 52.8 and 22.1 nM, respectively. By the assessments of the recombinant amylase and immunoprecipitation, the major binding protein of CS-1036 in rats was identified as salivary amylase (KD 5.64 nM). CS-1036 also showed concentration-dependent and saturable binding to human salivary and pancreatic amylase, with similar binding affinity in rats. However, the protein binding of CS-1036 was constant in human plasma (≤10.2%) due to the lower serum amylase level compared with rats and monkeys. From the calculation of the unbound fraction (fu) in plasma based on in vitro KD and Bmax, the dose-dependent increase in fu after oral administration is speculated to lead to a dose-dependent increase in total body clearance and a high area under the curve/dose at lower doses, such as 0.3 mg/kg in rats.
authors: Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan (T.H., Y.K.-U., T.It., T.Iz.); Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan (T.K.); Translational Medicine & Clinical Pharmacology Department, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.M., H.O.); and Global Project Management Department, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan (A.Y.).
authors: Tomohiro
authors: T
authors: Honda
authors: Yoko
authors: Y
authors: Kaneno-Urasaki
authors: Takashi
authors: T
authors: Ito
authors: Takako
authors: T
authors: Kimura
authors: Nobuko
authors: N
authors: Matsushima
authors: Hiromi
authors: H
authors: Okabe
authors: Atsushi
authors: A
authors: Yamasaki
authors: Takashi
authors: T
authors: Izumi
mesh_terms: D000328:Adult; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004187:Disaccharides / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008252:Macaca fascicularis; D008297:Male; D055292:Pancreatic alpha-Amylases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D011485:Protein Binding; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D055291:Salivary alpha-Amylases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D013045:Species Specificity; D014462:Ultrafiltration; D055815:Young Adult
chemical_list: C584005:4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxyglucopyranosyl)glucopyranoside; D001798:Blood Proteins; D004187:Disaccharides; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D011994:Recombinant Proteins; D055292:Pancreatic alpha-Amylases; D055291:Salivary alpha-Amylases