Effect of perfusion rate on the local disposition of cefixime in liver perfusion system based on two-compartment dispersion model.
The effect of perfusion flow rate upon the estimated parameters in the two-compartment (non-equilibrium) dispersion model, such as dispersion coefficient, volume of the blood space, partition ratio, and irreversible transfer (or elimination) rate constant, was evaluated in the rat liver perfusion system, using cefixime as a test drug. The rats were divided into five groups and the perfusion experiments were performed at various perfusion rates (Q = 6.4, 11.3, 14.1, 16.3, and 19.6 ml/min/liver). The two-compartment dispersion model was fitted to the outflow cefixime concentration profiles after bolus input into the portal vein using the nonlinear least squares program MULTI(FILT). Results of curve fitting suggested that the corrected dispersion coefficient (DC) and the volume of blood space (VB) increased with increase in flow rate. In contrast, the partition ratio (k'), which is a measure of the extent of drug partition between the blood and the hepatic tissues, decreased when flow rate increased. The single-pass extraction ratio of cefixime is small, and the irreversible transfer rate constant (ke) was independent of flow rate. These parameters were correlated to the moment characteristics such as the recovery ratio (FH), the mean hepatic transit time (tH), and the relative variance of the transit time (sigma 2/tH2). FH and sigma 2/tH2 were independent of the flow rate, whereas tH decreased and the apparent distribution volume (VH) increased with increase in perfusion rate.
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Y
Y
Yano
K
K
Yamaoka
H
H
Yasui
T
T
Nakagawa
D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000493:pharmacokinetics*; D020682:Cefixime; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008432:Mathematical Computing; D008954:Models, Biological; D010477:Perfusion / Q000379:methods*; D051381:Rats; D011919:Rats, Inbred Strains; D012044:Regression Analysis; D012984:Software
D000892:Anti-Infective Agents, Urinary; D020682:Cefixime; D002439:Cefotaxime