R. Azuma et al., First-pass of GTS-21 on canine gut wall and liver determined by portal-systemic concentration difference, EUR J PH SC, 14(2), 2001, pp. 159-165
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
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