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

• Published in: Drug metabolism and disposition Vol. 41; no. 4; pp. 878 - 887
• Main Authors: Honda, Tomohiro, Kaneno-Urasaki, Yoko, Murai, Takahiro, Kakuta, Masayo, Nasu, Hatsumi, Namba, Eiko, Koga, Tetsufumi, Okuno, Akira, Izumi, Takashi
• Format: Journal Article
• Language: English
• Published: United States 01-04-2013
• Subjects: Absorption; Administration, Oral; alpha-Amylases - antagonists & inhibitors; Animals; Biological Availability; Blood Glucose - drug effects; Disaccharides - administration & dosage; Disaccharides - pharmacokinetics; Disaccharides - pharmacology; Injections, Intravenous; Intestinal Absorption - drug effects; Macaca fascicularis; Male; Pyrrolidines - administration & dosage; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Rats; Tissue Distribution
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.112.050591

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.