Application of rat in situ single-pass intestinal perfusion in the evaluation of presystemic extraction of indinavir under different perfusion rates.
OBJECTIVE
First-pass effect has been an important concern for oral pharmaceuticals. An in vivo system was developed for measuring different concentrations of pharmaceuticals in the portal vein and hepatic vein (via the inferior vena cava) for delineating presystemic metabolism under different perfusion rates by using indinavir as an exemplary agent.


METHODS
An in situ single-pass intestinal perfusion technique was modified from previous studies to concomitantly obtain portal and hepatic venous bloods. Portal and hepatic venous samples were simultaneously taken from rats at appropriate time points using the perfusion model of 1 mg/mL indinavir at flow rates of 0.05, 0.1, 0.5 and 1.0 mL/min. The indinavir concentrations were assayed by binary-gradient high-pressure liquid chromatography with UV detection.


RESULTS
The mean indinavir concentrations in portal vein concentration-time profiles at different perfusion times under various flow rates were all higher than those obtained for hepatic veins. At flow rates of 0.5 and 1.0 mL/min, in particular, the area under the curve (AUC) and maximal concentration (Cmax) of indinavir absorption were significantly different between portal veins and hepatic veins (p < 0.05), indicating considerable hepatic involvement in the presystemic extraction of indinavir. The system also has potential for use when estimating the hepatic extraction ratio (E(H)) and hepatic clearance (Cl(H)).


CONCLUSIONS
This in vivo approach could provide another useful tool for improving our basic understanding of the absorption kinetics and hepatic metabolism of pharmaceuticals under development and facilitating the clinical application of such.
Ho
Yunn-Fang
YF
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. yfho@ntu.edu.tw
Lai
Ming-Yen
MY
Yu
Hsiu-Ying
HY
Huang
Da-Kong
DK
Hsueh
Wei-Cherng
WC
Tsai
Tung-Hu
TH
Lin
Chia-Chun
CC
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D019469:Indinavir / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D017320:HIV Protease Inhibitors; D019469:Indinavir