Abstract

Recently, analytical methods have become available for determination of both the lactone (active form) and the carboxylate (inactive form) forms of 20(S)-camptothecin in biological fluids. Studies in our laboratory have shown that there are significant differences in the in vivo behavior of the two forms of camptothecin and that much higher plasma levels of the lactone form are present in rats after dosing with camptothecin (lactone) than after dosing with the sodium salt of the ring-opened camptothecin (carboxylate form). The present studies show that there are significant differences in the urinary and biliary elimination of the two forms and that the urinary excretion of the carboxylate form appears to be pH dependent. This apparent pH dependence of the urinary elimination of the carboxylate form may provide a method of reducing the bladder toxicity associated with the use of camptothecin. After administration of a 1 mg/kg iv dose of camptothecin (lactone) to rats, 10.1 +/- 4.2% of the dose was excreted into the urine and 7.5 +/- 4.2% of the dose was excreted into the bile. Following an equivalent intravenous dose of the carboxylate form, 39.5 +/- 10.4% of the dose was excreted into the urine and 26.4 +/- 8.9% of the dose was excreted into the bile.