Preclinical pharmacology of the natural marine product dolastatin 10 (NSC 376128)

The preclinical pharmacology and pharmacokinetics of the natural marine product dolastatin 10 were investigated. Pharmacokinetics of [3H]dolastatin 10 were determined in CD2F1 mice after intravenous, subcutaneous, and intraperitoneal routes of administration. After intravenous injection (0.24 mg/kg), plasma drug concentration declined rapidly and was cleared from plasma with a half-life of 5.6 hr. After a subcutaneous dose of 0.32 mg/kg, dolastatin 10 concentrations slowly rose to a maximum of 11 ng/ml and then declined with an elimination half-life of 3.7 hr. Most of the radioactivity in plasma was found to be from drug-derived radiolabeled products and not from parent compound. Urinary excretion of dolastatin 10 was < 2% of the administered dose, irrespective of the route of administration. In vitro, dolastatin 10 was stable in mouse plasma for at least 24 hr at 37 degrees C. The drug was also highly protein-bound (> 81%) in human, dog, and mouse plasmas. Dolastatin 10 underwent rapid conversion to more polar products after incubation with whole liver homogenate or the S9 fraction from rate liver. One of these metabolites was identified by mass spectrometry as a dihydroxy derivative of dolastatin 10.