Zonal compartmentation of perfused rat liver: plasma reappearance of rhodamine B explained.
Rhodamine B (RB) fluorescence reappears in perfusion medium of a cyclically perfused rat liver after a rapid initial removal phase. At the same time the compound redistributes in the liver from acinar zone 1 toward zone 3. By analysis of the metabolic profile of RB, and by inhibition of glucuronidation (the main metabolic route) with salicylamide, we show in this paper that formation and secretion of RB-conjugates from liver into perfusate is not involved in the reappearance and redistribution phenomena. We therefore sought the explanation in a kinetic model, in which the acinar heterogeneity of the liver was simulated by several sequential liver compartments. Most kinetic parameters we used in the simulation were calculated from previous experiments with RB (Braakman et al., Hepatology 7: 849-855, 1987). This led to an accurate simulation of the measured RB curves in bile, medium and the acinar zones of the liver. In this study we show that a secondary rise in medium concentration of an injected compound is not necessarily caused by metabolism, but can be easily explained by considering the liver a sequence of compartments, instead of one well-stirred compartment. The conditions for the reappearance as well as for the intrahepatic redistribution are: a fast uptake into the liver, combined with a fast sinusoidal secretion and a slow biliary excretion of the injected substance.
Braakman
I
I
Department of Pharmacology and Therapeutics, University of Groningen, The Netherlands.
Groothuis
G M
GM
Meijer
D K
DK
D000818:Animals; D003198:Computer Simulation; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D012235:Rhodamines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D012457:Salicylamides / Q000494:pharmacology; D014966:Xanthenes / Q000493:pharmacokinetics*
D012235:Rhodamines; D012457:Salicylamides; D014966:Xanthenes; C031060:salicylamide; C029773:rhodamine B