Effects of atorvastatin, an HMG-CoA reductase inhibitor, on hepatic oxidative metabolism of antipyrine

Possible effects of multiple-dose administration of atorvastatin on the pharmacokinetics of single-dose antipyrine were evaluated in this drug-drug interaction study. Twelve healthy male volunteers received three 200-mg capsules of antipyrine on days 1 and 22, and two 40-mg atorvastatin tablets in the morning on days 8 through 23, Serial blood and urine samples were collected after administration of each antipyrine dose. Plasma was analyzed for antipyrine, and urine samples were analyzed for antipyrine, 4-hydroxyantipyrine, and norantipyrine by validated high-performance liquid chromatography with ultraviolet detection. Overall, antipyrine and atorvastatin doses were well tolerated in healthy volunteers. Mean antipyrine concentrations in plasma after administration of a single, oral dose of antipyrine during coadministration of multiple doses of atorvastatin were nearly superimposible on concentrations after administration of antipyrine alone. Individual and mean parameter values for plasma pharmacokinetics of antipyrine were similar in both treatment periods. Atorvastatin did not significantly alter the fraction of clearance of antipyrine in plasma that occurred by urinary excretion of 4-hydroxyantipyrine and norantipyrine. These results indicate that the recommended highest daily dose of atorvastatin has negligible effects on antipyrine pharmacokinetics and on oxidative pathways responsible for the metabolism of antipyrine.