Pharmacokinetic studies of AY4166 (4): Metabolism of ¹⁴C-AY4166 in rats and dogs

Metabolism of the AY4166, a novel antidiabetic agent, was studied both in vivo and in vitro. 1) When ¹⁴C-AY4166 was orally administrated to rats, a half of radioactivity detected in plasma at 0.5 hr after administration, accounted for the unchanged AY4166. The major metabolites in rat plasma were M1 (25%), the methine hydroxylated product, M2 & M3(about 20% by mixture), the optical isomer of the methyl hydroxylated products. In the liver and kidney, major parts of radioactivity were presented as metabolites M1, M2 and M3. On the other hand, when "C-AY4166 was orally administrated to dogs, more than 90% of radioactivity was presented as the unchanged AY4166 at 30 min and 4 hr. 2) After oral administration of ¹⁴C-AY4166 to rats, five metabolites were identified in the urine and the bile. The main metabolite excreted in urine was M1(47.3%) followed by M2 & M3 and carboxyl derivatives, M9 & M10 which were supposed to be generated from M2 & M3 by oxidation. The main metabolites in bile were M9 & M10(43.1%) followed by M2 & M3 and M1. After oral administration of ¹⁴C-AY4166 to dogs, five more metabolites than rats were identified in the urine and in the bile. The major component excreted in bile was unchanged AY4166 followed by three glucuronic acid conjugates (M4, M5 & M6) , dehydro derivative (M7), hydroxyl derivative (M8) and M9 & M10. 3) The interaction in vitro of AY4166 with MFO S9 fraction were studied using rat liver, kidney, duodenum, pancreas S9 fraction and plasma. In liver and kidney, three oxidative metabolites, M1, M2 & M3 and two carboxylic metabolites, M9 & M10 were formed, but in plasma, duodenum and pancreas no metabolite was formed. 4) Hypoglycemic effect of metabolites was compared with that of AY4166 in maximum blood glucose level reducing activity. It was observed, M1 was about five-six times less potent and M2 & M3 were three times less potent than AY4166, while M7 was almost as potent as AY4166.