IDENTIFICATION OF TISSUES RESPONSIBLE FOR THE CONJUGATIVE METABOLISM OF LIQUIRITIGENIN IN RATS - AN ANALYSIS BASED ON METABOLITE KINETICS

We kinetically examined tissues responsible for the conjugative metabo lism (glucuronidation and sulfation) of a component in a crude drug, l iquiritigenin (LG; oxy-2-(4-hydroxyphenyl)-(S)-4H-1-benzopyran-4-one) in rats in vivo. LG has been found to form five kinds of conjugates (4 '-O-glucuronide (M1), 7-O-glucuronide (M2), 4',7-O-disulfate (M3), 4'- O-glucuronide-7-O-sulfate (M4) and 7-O-glucuronide-4'-O-sulfate (M5)). Analysis based on metabolite kinetics [K. S. Pang, J. Pharmacokin. Bi opharm., 13, 633 (1985)] of the area under the plasma concentration cu rves (AUC(plasma)) and cumulative biliary excretions (Ai(bile)) of the ligands after intravenous or hepatic portal venous administration of LG revealed that the liver has the ability to generate all the metabol ites. For M1 and M2, the apparent biliary excretion clearance (CL(bile , app)) obtained by dividing the biliary excretion rate for the metabo lite by the plasma concentration of the metabolite decreased with time , confirming that M1 and M2 were formed in the liver. To further analy ze the formation rate constants for metabolites in each tissue, we mea sured the ligand content in several tissues after intravenous administ ration of LG. By correcting the content of metabolites that were taken up from the plasma, we found that the formation rates per gram of tis sue were largest in the liver, except for M3. The metabolic capability of the kidney for M1 and M2 was 15% and 60%, respectively, to that of the liver whereas for M3, the metabolic ability of the kidney was 2.5 -fold greater than that of the liver. In contrast, the ability in othe r tissues was negligible. Considering the weight of each organ in rats , the liver was most responsible for the formation of metabolites, exc ept for M3, where renal conjugation was comparable to hepatic conjugat ion. The order of formation rate in the liver was M2 > M1 >> M3, M4 an d M5, while that in the kidney was M2 >> M1 and M3. These results were supported by experiments in hepatectomized rats. We could thus quanti tatively estimate the formation rate constant for each metabolite in e ach organ in vivo.