Effects of endotoxin on the pharmacology of antineoplastic agents.

Patients with cancer often develop serious gram-negative bacterial infections. Since bacterial endotoxins have been shown to affect the in vitro hepatic metabolism of antineoplastic agents, significant infection may adversely affect drug pharmacokinetics and metabolism in these patients. To evaluate the clinical significance of these effects, bacterial endotoxin (0.5 mg/kg, IV) was administered to male beagle dogs 1 or 24 h prior to the administration of radiolabeled 5-fluorouracil (5-FU), methotrexate (MTX), arabinosylcytosine (Ara-C), or vinblastine (VLB) as an IV bolus. Drug levels in plasma and urine were measured at various times after administration and standard pharmacokinetic parameters were calculated. The pharmacokinetics of all four agents were found to be significantly altered by the administration of bacterial endotoxin. However, there were no detectable patterns to these changes so that no predictions could be made. In studies on rats, chronic, nonlethal endotoxin administration (0.8 mg . kg-1 . day-1 for 10 days) resulted in a dramatic decrease in the distribution of [14C]methylglyoxal bis(guanylhydrazone) (MGBG) in liver, kidney, intestine, heart and lung tissue. This suggests that bacterial endotoxin may also effect drug pharmacokinetics by altering drug penetration into various organs. In studies on hepatic microsomes isolated from rats, bacterial endotoxin incubation affected aniline hydroxylase activity only at concentrations greater than 0.4 mg/ml, at least tenfold higher than the LD 50 of endotoxin in rats. It therefore seems likely that the endotoxin may require in vivo metabolism to affect changes in drug metabolism and disposition.