Pharmacokinetics of homoharringtonine in dogs.

We studied the pharmacokinetics and distribution of homoharringtonine (HHT), an antitumor alkaloid, in anesthetized dogs using chromatographic and radiochemical techniques. Uniformly tritiated HHT was administered i.v. to five dogs at doses of 0.05 to 0.34 mg/kg, 200 microCi per animal. Unchanged HHT disappeared in a triphasic manner from the plasma with an initial plasma t1/2 of 9.4 +/- 4.2 min, an intermediary t1/2 of 1.4 +/- 0.5 h, and a terminal t1/2 of 40.6 +/- 4.6 h. The plasma clearance was 114.0 +/- 20.1 ml/kg-1 h-1 and the steady-state volume of distribution was 6.2 +/- 0.7 1/kg. In 72 h, 40.1% +/- 4.0% of the administered radioactivity was excreted in the urine, 17.8% +/- 2.7% of which was unchanged HHT. HHT was metabolized extensively to one major and two minor metabolites. Biliary excretion of total radioactivity was 14.4% in 5 h, 2% of which was HHT. HHT concentration in the CSF was highest 4 h after drug administration, about 40% of the concentration in the concurrent plasma. At autopsy 5 h after dosing, the highest percentage of HHT was in the liver (7.4%), followed by the small intestine (2.5%), stomach (1.0%), pancreas (0.8%), kidneys (0.8%), and lungs (0.7%). The heart, spleen, large intestine, and brain each retained less than 0.5%. However, 24 h after dosing, 4% of the HHT still remained in the liver, 1% in the small intestine, and less than 1% in the other organs. HHT seems to be extensively metabolized in dogs and partially retained in the body.