title: Absorption, elimination, and metabolism of CS-1036, a novel α-amylase inhibitor in rats and monkeys, and the relationship between gastrointestinal distribution and suppression of glucose absorption.
abstract: The absorption, metabolism, and excretion of (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-d-glucopyranosyl)-α-d-glucopyranoside (CS-1036), a novel and potent pancreatic and salivary α-amylase inhibitor, were evaluated in F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of CS-1036 were low (2.67-3.44 ml/min/kg and 0.218-0.237 l/kg for rats and 2.25-2.84 ml/min/kg and 0.217-0.271 l/kg for monkeys). After intravenous administration of [(14)C]CS-1036 to rats and monkeys, radioactivity was mainly excreted into urine (77.2% for rats and 81.1% for monkeys). After oral administration, most of the radioactivity was recovered from feces (80.28% for rats and 88.13% for monkeys) with a low oral bioavailability (1.73-2.44% for rats and 0.983-1.20% for monkeys). In rats, intestinal secretion is suggested to be involved in the fecal excretion as a minor component because fecal excretion after intravenous administration was observed (15.66%) and biliary excretion was almost negligible. Although intestinal flora was involved in CS-1036 metabolism, CS-1036 was the main component in feces (70.3% for rats and 48.7% for monkeys) and in the intestinal contents (33-68% for rats up to 2 hours after the dose) after oral administration. In Zucker diabetic fatty rats, CS-1036 showed a suppressive effect on plasma glucose elevation after starch loading with a 50% effective dose at 0.015 mg/kg. In summary, CS-1036 showed optimal pharmacokinetic profiles: low oral absorption and favorable stability in gastrointestinal lumen, resulting in suppression of postprandial hyperglycemia by α-amylase inhibition.
authors: Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan. honda.tomohiro.us@daiichisankyo.co.jp
authors: Tomohiro
authors: T
authors: Honda
authors: Yoko
authors: Y
authors: Kaneno-Urasaki
authors: Takahiro
authors: T
authors: Murai
authors: Masayo
authors: M
authors: Kakuta
authors: Hatsumi
authors: H
authors: Nasu
authors: Eiko
authors: E
authors: Namba
authors: Tetsufumi
authors: T
authors: Koga
authors: Akira
authors: A
authors: Okuno
authors: Takashi
authors: T
authors: Izumi
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects*; D004187:Disaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D014018:Tissue Distribution; D000516:alpha-Amylases / Q000037:antagonists & inhibitors*
chemical_list: C584005:4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxyglucopyranosyl)glucopyranoside; D001786:Blood Glucose; D004187:Disaccharides; D011759:Pyrrolidines; D000516:alpha-Amylases