RT Journal Article
SR Electronic
T1 Tissue Distribution and Identification of Radioactivity Components at Elimination Phase after Oral Administration of [14C]CS-1036, an α-Amylase Inhibitor, to Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1125
OP 1133
DO 10.1124/dmd.112.050617
VO 41
IS 5
A1 Tomohiro Honda
A1 Hideo Takakusa
A1 Takahiro Murai
A1 Takashi Izumi
YR 2013
UL http://dmd.aspetjournals.org/content/41/5/1125.abstract
AB (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.