Human pharmacokinetics of a new acridine derivative, 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992).

The clinical pharmacology of 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine) was studied, utilizing [9-14C]amsacrine i.v. in 19 patients with disseminated neoplasms. The mean terminal plasma half-life for total 14C ranged from 34 hr in patients with normal organ function to 46 hr in patients with severe liver disease. For unchanged amsacrine, the mean values of plasma half-life were 7.4 and 17.2 hr for patients with normal and abnormal liver function, respectively. The plasma half-lives of 14C were prolonged, while those for unchanged amsacrine appeared to be normal in patients with renal dysfunction. The mean 72-hr cumulative urinary excretion of total 14C varied from 35% in normal patients to 49% in patients with severe liver disease, while patients with renal disease excreted only 2 to 16%. In comparison, the urinary excretion of unchanged amsacrine was 12, 20 and 2% of the administered dose, respectively, in these same patients. Amsacrine biliary excretion studied in two patients showed about 8 and 36% of the administered radioactivity excreted in the bile in 72 hr, with less than 2% as unchanged amsacrine. Cerebrospinal fluid concentrations of amsacrine were below 2% of the simultaneous plasma levels in three patients. Impaired amsacrine drug clearance was frequently associated with liver dysfunction. Patients with impaired amsacrine drug clearance experienced the most severe clinical toxicity. Hepatic metabolism and biliary excretion appear the most important routes for amsacrine elimination. Renal elimination, although less important, is significant in patients with severe kidney dysfunction. To avoid excessive clinical toxicity, initial dose reductions of 30 to 40% are recommended for patients with severe liver or renal disease or for those who have pharmacologically documented impaired drug clearance.