title: Tissue distribution and identification of radioactivity components at elimination phase after oral administration of [¹⁴C]CS-1036, an α-amylase inhibitor, to rats.
abstract: (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036) is a potent inhibitor of pancreatic and salivary α-amylase. After oral administration of [¹⁴C]CS-1036 to rats, the radioactivity was still detectable up to 7-14 days after administration in various tissues, and its terminal phase in plasma could be explained neither by the exposure of CS-1036 nor its major metabolite M1. The slow elimination of radioactivity in various tissues was hypothesized to be caused by covalent binding to macromolecules or use for biogenic components. To assess the use for biogenic components, amino acid analysis of plasma proteins and lipid analysis of adipose tissue were conducted after repeated oral administration of [¹⁴C]CS-1036 by high-performance liquid chromatography and accelerated mass spectrometry and by thin layer chromatography and liquid chromatography/mass spectrometry, respectively. In amino acid analysis, glutamic acid, aspartic acid, alanine, and proline were identified as major radioactive amino acids, and radioactive nonessential amino acids occupied 76.0% of the radioactivity. In lipid analysis, a part of the radioactive lipids were identified as the fatty acids constituting the neutral lipids by lipase-hydrolysis. The radioactive fatty acids from neutral lipids were identified as palmitic acid, oleic acid, and 8,11,14-eicosatrienoic acid. Intestinal flora were involved in CS-1036 metabolism and are indicated to be involved in the production of small molecule metabolites, which are the sources for amino acids and fatty acids, from [¹⁴C]CS-1036. In conclusion, radioactivity derived from [¹⁴C]CS-1036 was incorporated as the constituents of amino acids of plasma proteins and fatty acids of neutral lipids.
authors: Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. honda.tomohiro.us@daiichisankyo.co.jp
authors: Tomohiro
authors: T
authors: Honda
authors: Hideo
authors: H
authors: Takakusa
authors: Takahiro
authors: T
authors: Murai
authors: Takashi
authors: T
authors: Izumi
mesh_terms: D000284:Administration, Oral; D000596:Amino Acids / Q000097:blood; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004187:Disaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005227:Fatty Acids / Q000097:blood; D006868:Hydrolysis; D008297:Male; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011874:Radiometry; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D000516:alpha-Amylases / Q000037:antagonists & inhibitors*
chemical_list: C584005:4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxyglucopyranosyl)glucopyranoside; D000596:Amino Acids; D004187:Disaccharides; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011759:Pyrrolidines; D000516:alpha-Amylases