URINARY AND BILIARY DISPOSITION OF THE LACTONE AND CARBOXYLATE FORMS OF 20(S)-CAMPTOTHECIN IN RATS

Recently, analytical methods have become available for determination o f both the lactone (active form) and the carboxylate (inactive form) f orms of 20(S)-camptothecin in biological fluids. Studies in our labora tory 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 campt othecin (lactone) than after dosing with the sodium salt of the ring-o pened camptothecin (carboxylate form). The present studies show that t here are significant differences in the urinary and biliary eliminatio n of the two forms and that the urinary excretion of the carboxylate f orm appears to be pH dependent. This apparent pH dependence of the uri nary elimination of the carboxylate form may provide a method of reduc ing the bladder toxicity associated with the use of camptothecin. Afte r administration of a 1 mg/kg iv dose of camptothecin (lactone) to rat s, 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 in travenous 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 in to the bile.