HEPATO-BILIARY TRANSPORT OF AMARANTH BY SINGLE PASS LIVER PERFUSION IN NORMAL AND CARBON TETRACHLORIDE OR α-NAPHTHYLISOTHIOCYANATE TREATED RATS

Abstract

Hepato-biliary transport of amaranth (AM) in normal and carbon tetrachloride (CCl₄) or α-naphthylisothiocyanate (ANIT) treated rats was studied using single pass liver perfusion. CCl₄-intoxicated rats were prepared by two different methods. One was a subcutaneous injection (CCl_{4 s.c.}) and the other was an oral administration (CCl_4p.o.). Though AM had been recognized to be non-metabolized in the liver, AM has been reported to be metabolized via azo-reduction by intestinal microflora and/or in the liver to yield naphthionic acid (1-amino-4-naphthalene sulfonic acid) (NSA) after oral administration. In the present investigation, AM was metabolized also in the perfused rat liver to yield NSA, which was not excreted in the bile, but effluxed into the effluent. The hepatic clearance of AM was significantly decreased in all intoxicated livers compared with the untreated livers. The concentration of NSA effluxed in the effluent was decreased in CCl_4s.c.-intoxicated livers. However, in other intoxicated livers, there was no significant difference from the untreated livers in the concentration of NSA in the effluent. The amount of AM excreted in the bile was significantly decreased in CCl_4s.c.-or CCl_4p.o.-intoxicated livers. In ANIT-intoxicated livers, no bile excretion was observed because of the biliary stagniation. From the results of pharmacokinetic analysis using a five-compartment model, the metabolism was not altered by all treatments investigated in the present study. Subcutaneous administration of CCl₄, which caused a mild intoxication, affected only the permeability of the plasma membrane of the liver to AM, but oral administration of CCl₄, which caused a severe intoxication, decreased the biliary excretion of AM as well as increased the permeability. ANIT-intoxication increased the permeability of plasma membrane of the liver to AM.