Evaluation of capacity-limited first-pass effect through liver by three-points sampling in portal and hepatic veins and systemic artery.
OBJECTIVE
The three-points method was newly developed by sampling the portal and hepatic veins and systemic artery. A model of hepatic local disposition with the Michaelis-Menten elimination was proposed to explain the concentration dependency of the hepatic recovery ratio (F(H)).


METHODS
5-fluorouracil (5-FU) was selected as a model drug. 5-FU was administered orally 90 min after its intraarterial dose. Blood specimens in both femoral artery and hepatic vein were sampled after intraarterial dose, and blood specimens in both femoral artery and portal vein were taken after oral administration.


RESULTS
It was shown that F(H) increased with an increase in the input drug concentration into the liver. The mean absorption time (MAT) estimated by nonlinear analysis agreed with the mean local absorption time (t(n)) whereas MAT by linear analysis was significantly smaller than t(a).


CONCLUSIONS
The three-points method was newly developed, and the proposed nonlinear model explained well the capacity-limited elimination of 5-FU through the liver. MAT by the nonlinear analysis was in good agreement with t(a).
Ueda
Shinya
S
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Yamaoka
Kiyoshi
K
Yui
Jyoji
J
Shigematsu
Akio
A
Nakagawa
Terumichi
T
D000818:Animals; D004353:Drug Evaluation, Preclinical; D005263:Femoral Artery / Q000378:metabolism*; D005472:Fluorouracil / Q000493:pharmacokinetics; D006503:Hepatic Veins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D017711:Nonlinear Dynamics; D011169:Portal Vein / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D005472:Fluorouracil