The pharmacokinetics of topotecan and its carboxylate form following separate intravenous administration to the dog.

PURPOSE

To determine the relationship between topotecan and its ring opened hydrolysis product (SK&F 105,992) following intravenous administration of the two agents separately, and to determine the bio-availability of topotecan in female beagle dogs.

METHODS

The pharmacokinetics of topotecan and SK&F 105,992 were determined following separate administration as 30 minute intravenous infusions in a cross-over design. Topotecan was also administered orally to the same dogs.

RESULTS

When administered intravenously to dogs, SK&F 105,992 underwent interconversion to topotecan. Plasma concentrations of both topotecan and SK&F 105,992 appeared to decline multi-exponentially following i.v. infusion of either compound. A 2-compartment model was found to adequately characterize the data.

CONCLUSIONS

The clearance of topotecan by other routes proceeded at a faster rate than its interconversion to SK&F 105,992, whereas the clearance of SK&F 105,992 by other routes was slower than the rate of its interconversion to topotecan. Any SK&F 105,992 formed in the GI tract did not appear to be well absorbed following oral administration of topotecan to dogs. The steady-state volume of distribution for topotecan was approximately 8- to 9-fold greater than that for SK&F 105,992 in the dog. After intravenous administration of topotecan, the amount of topotecan in the dog was much greater than that of the carboxylate, even though their respective plasma concentrations were similar. The bioavailability of topotecan, calculated from oral topotecan data or from SK&F 105,992 data, was approximately 50%.