The absorption and metabolism by the rat intestine of the tetrazole-containing angiotensin II receptor antagonist losartan were determined using in vitro, in situ and in vivo models of absorption. The permeability coefficient of losartan was similar at mucosal concentrations of 0.5 to 2 mM when assayed using segments of jejunum in the Sweetana/Grass diffusion cell. The compound was conjugated during transport to form a glucuronide at the N2-position of the tetrazole group; the structure was confirmed by LC/MS/MS. Approximately 12% to 20% of losartan transported across the duodenum and jejunum was conjugated to the glucuronide. The glucuronide was not detected when sections of the ileum or colon were used. In the in situ intestinal loop model, 18% to 23% of the losartan injected into the lumen was recovered in the mesenteric vein by 1 hr. As in the in vitro model, 11% to 15% of the compound was conjugated on the tetrazole group during absorption. EXP-3174, the pharmacologically active carboxylic acid metabolite of losartan, was not detected in either the serosal buffer from the in vitro study or the mesenteric plasma from the in situ intestinal loop. In conscious rats, N2-glucuronide was detected in plasma samples from the portal vein soon after oral administration of losartan. It was detected at low concentrations in only a few of the arterial samples assayed. In conclusion, losartan is conjugated with glucuronic acid at the N2-position of the tetrazole group during absorption by the rat upper gastrointestinal tract.