CLOFIBRATE DISPOSITION IN RENAL-FAILURE AND ACUTE AND CHRONIC LIVER-DISEASE

The disposition of clofibrate [one of the most effective drugs for lowering plasma triglyceride and cholesterol level in man] over 96 h was observed following single oral dose in 6 patients with acute viral hepatitis, 6 patients with liver cirrhosis, 7 patients with renal insufficiency, and 6 control subjects. No parameter of the disposition of CPIB (chlorophenoxyisobutyric acid, the active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the nonprotein bound drug was reduced (115 vs. 243 ml .times. min-1), plasma protein binding was reduced (92.8 vs. 97.2%), and the apparent volume of distribution was increased (0.20 vs. 0.141 .times. kg-1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml .times. min-1) and plasma clearance of the unbound drug (81 vs. 243 ml .times. min-1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should evidently be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.