Alpha-amylase inhibitor, CS-1036 binds to serum amylase in a concentration-dependent and saturable manner
| Autor: | Kimura Takako, Hiromi Okabe, Nobuko Matsushima, Tomohiro Honda, Atsushi Yamasaki, Yoko Kaneno-Urasaki, Takashi Ito, Takashi Izumi |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.medical_specialty Pyrrolidines Immunoprecipitation Pharmaceutical Science Alpha amylase inhibitor Ultrafiltration Plasma protein binding Pancreatic alpha-Amylases Disaccharides Rats Sprague-Dawley Young Adult Double-Blind Method Species Specificity Oral administration Internal medicine medicine Escherichia coli Animals Humans Amylase Enzyme Inhibitors Pharmacology biology Dose-Response Relationship Drug Chemistry Binding protein Area under the curve Blood Proteins Rats Inbred F344 Recombinant Proteins Rats Dose–response relationship Macaca fascicularis Endocrinology Salivary alpha-Amylases biology.protein Protein Binding |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 42(3) |
| ISSN: | 1521-009X |
| Popis: | (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. |
| Databáze: | OpenAIRE |
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