AbstractEight beagle dogs received [3H]VP 16–213 at 2 mg/kg administered intravenously (IV) or intra-arterially (IC) through a catheter inserted into the internal carotid artery. Blood, urine, bile, and cerebrospinal fluid (CSF) samples were collected at intervals. At 1, 6, 24 hr, and 2 weeks after drug administration the dogs were sacrificed and the major organs analyzed for drug concentration. VP 16–213 concentration was determined by radiochemical assay and high pressure liquid chromatography. The plasma t1/2in the IC group of dogs was 1.0 hr, the volume of distribution was I.7 L/kg and the clearance was 1.5 ml/hr/kg. In the IV group the values were 1.7, 3.9, and 1.6, respectively. The CSF concentration peaked at I hr by both routes, but was higher at all time points in the IC group. At 24 hr and 2 weeks after IC VP 16–213, drug concentration in brain tissue was at least four times higher in the IC group compared with the IV group. In extracranial organs the reverse was true, with the bone marrow cell concentration 1.6 times higher by IV compared to IC (267.2 ng/g and 164.5 ng/g, respectively). Two major and one minor metabolites were found in plasma, urine, bile, and tissue by both routes, however, not all metabolites were found in all organs and body fluids. No acute neurologic toxicity was noted in the IC group and no histopathologic changes by light microscopy were found in the brain or other organs. IC VP 16–213 produced higher drug concentration in the brain of dogs compared with IV administration and was well tolerated at the dosage used.