ABSORPTION AND GLUCURONIDATION OF THE ANGIOTENSIN-II RECEPTOR ANTAGONIST LOSARTAN BY THE RAT INTESTINE

The absorption and metabolism by the rat intestine of the tetrazole-co ntaining angiotensin II receptor antagonist losartan were determined u sing in vitro, in situ and in vivo models of absorption. The permeabil ity coefficient of losartan was similar at mucosal concentrations of 0 .5 to 2 mM when assayed using segments of jejunum in the Sweetana/Gras s diffusion cell. The compound was conjugated during transport to form a glucuronide at the N-2-position of the tetrazole group; the structu re was confirmed by LC/MS/MS. Approximately 12% to 20% of losartan tra nsported across the duodenum and jejunum was conjugated to the glucuro nide. The glucuronide was not detected when sections of the ileum or c olon were used. In the in situ intestinal loop model, 18% to 23% of th e losartan injected into the lumen was recovered in the mesenteric vei n by 1 hr. As in the in vitro model, 11% to 15% of the compound was co njugated on the tetrazole group during absorption. EXP-3174, the pharm acologically active carboxylic acid metabolite of losartan, was not de tected in either the serosal buffer from the in vitro study or the mes enteric plasma from the in situ intestinal loop. In conscious rats, N- 2-glucuronide was detected in plasma samples from the portal vein soon after oral administration of losartan. It was detected at low concent rations in only a few of the arterial samples assayed. In conclusion, losartan is conjugated with glucuronic acid at the N-2-position of the tetrazole group during absorption by the rat upper gastrointestinal t ract.