GLUTATHIONE KINETICS IN NORMAL MAN AND IN PATIENTS WITH LIVER-CIRRHOSIS

Background/Aims: The dynamics of glutathione in plasma has always been studied by bolus injections. Data are available suggesting that the l ow plasma levels of cirrhosis are due to decreased production in gluta thione-producing tissues, mainly the liver, We aimed to measure the ki netics of glutathione during controlled steady-state conditions, and t o determine the reasons for its reduced plasma levels in advanced cirr hosis. Methods: The plasma clearance of glutathione was measured in si x control subjects and in ten patients with cirrhosis during a 2-step infusion study, producing steady-state levels approximately 5 and 10 t imes basal values, The plasma disappearance curve after infusion stop was used to determine the apparent volume of distribution and half-lif e of glutathione, and the estimated basal appearance rate. Results: Th e clearance of glutathione did not reject Ist-order kinetics, i.e., it was concentration-independent, and was nearly doubled in cirrhosis. T he half-life of exogenous glutathione was not different, whereas the v olume of distribution was larger in cirrhosis, in the same range as ex tracellular water, The endogenous basal appearance rate of glutathione was reduced by 50%, and correlated with liver function, measured by r outine and dynamic tests. Conclusions: The data confirm that the prima ry defect responsible for reduced glutathione in liver disease is a re duced production, possibly related to hepatocyte dysfunction and a blo ck along the pathway of methionine metabolism.