First-pass of GTS-21 on canine gut wall and liver determined by portal-systemic concentration difference

To clarify the cause of the canine individual variability of plasma concent ration after oral administration of GTS-21 [(E)-3-(2,4-dimethoxybenzylidene ) -3,4,5,6-tetra-hydro-2,3 ' -bipyridine dihydrochloride ], we evaluated th e absorption ratio (F-A), intestinal availability (F-G), and hepatic availa bility (F-H). The bioavailability (F) was evaluated from the ratio of the a rea under the plasma concentration versus time curves after oral and intrav enous administration. Three isoflurane anaesthetised dogs were fitted with an electromagnetic flow probe attached to the portal vein and cannulated th rough the portal and the femoral veins. After intraduodenal administration of GTS-21, both plasma concentrations were determined simultaneously. F-A.F -G was calculated from the portal-systemic concentration difference taking into consideration the blood-plasma partition ratio. F, was calculated from the residual drug contents of the small intestine. F-H was calculated by d ividing F by F-A.F-G. The F values were 0.072, 0.021, and 0.037, indicating an individual variability of ca. threefold. The F-A values were close to 1 , and the F-G values ranged from 0.449 to 0.461. Accordingly, the Fu values were estimated at 0.170, 0.047, and 0.083. GTS-21 was completely absorbed but lost by first-pass effects of passage through the gut wall and liver. T he first-pass effect of liver is larger than that of the gut wall, and domi nates the individual variability in plasma concentration. (C) 2001 Elsevier Science BY All rights reserved.