TY - JOUR T1 - Absorption, Elimination, and Metabolism of CS-1036, a Novel <em>α</em>-Amylase Inhibitor in Rats and Monkeys, and the Relationship between Gastrointestinal Distribution and Suppression of Glucose Absorption JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 878 LP - 887 DO - 10.1124/dmd.112.050591 VL - 41 IS - 4 AU - Tomohiro Honda AU - Yoko Kaneno-Urasaki AU - Takahiro Murai AU - Masayo Kakuta AU - Hatsumi Nasu AU - Eiko Namba AU - Tetsufumi Koga AU - Akira Okuno AU - Takashi Izumi Y1 - 2013/04/01 UR - http://dmd.aspetjournals.org/content/41/4/878.abstract N2 - 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 [14C]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. ER -