Abstract
Impaired drug metabolisms patients with liver injury were investigated by measuring pharmacokinetics of several drugs on high performance liquid chromatography. The drugs tested were an anti-canceragent [1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207)], an immunosuppressive agent [azathioprine (AZP)] and an antibiotics [cefazolin (CEZ)], which were metabolized differently in liver and played important effects in vivo. The K values following an intravenous injection of FT-207 (KF) decreased significantly in cirrhotic patients with primary hepatoma. In these patients with continuous oral administrations of the drug, the blood levels gradually increased day by day to the levels higher than 10μg/ml. The KF values were significantly correlated withKim values.
Increases in the KF values by pretreating with tocopheryl nicotinate and reduced glutathione were observed in cancer patients without liver involvements but not in cirrhotic patients with hepatoma, indicating difficult amplification of masked-compound efficacy in patients with advanced liver injury. The K values of CEZ(KC), which were excreted mainly in urine, decreased even in cirrhotic patients, especially, with ascites. The impaired metabolisms of CEZ may be related to altered renal functions due to associated hepatorenal syndrome but not to severity of liver injury, since endogenous creatinine clearance and urine volume were correlated with KC measured. The metabolisms of AZP in vivo was impaired in rats pretreated with probenecid or carbontetrachloride, in which glutathione S-transferase activities markedly diminished, indicating that AZP efficacy as an immunosuppressing agent could not be expected sufficiently in subjects with severe liver injury. These results suggest that individual measurement of each drug pharmacokinetics is necessary for planning an optimal dose administered to each of patients with liver injury.
