This study was conducted to determine the uptake of dihydroergotamine (DHE) into the brain after intravenous and intranasal administration in rats. Eight anesthetized rats received either an intravenous (i.v.) or two successive intranasal (i.n.) doses of tritium labeled dihydroergotamine ( 3 H-DHE) with 14 C-inulin as a non-BBB (blood-brain barrier) permeable marker. Radioactivity concentrations in plasma were determined at designated times within 30 min postdose, and in blood and seven brain regions (olfactory bulb, frontal cortex, parietal cortex, occipital cortex, cerebellum, mid-brain areas, and brain stem) at 30 min. The plasma-to-brain permeabilityarea product (PeA) following an i.v. dose was calculated based on the 30-min brain tissue concentration and the area under the plasma concentrationtime curve (AUC 0 -30 min, i.v. ) assuming unidirectional transport from plasma to brain. Direct transport from nasal cavity to brain was assessed based on the amount of radioactivity in brain determined experimentally and predicted based on plasma AUC 0 -30 min, i.n. and PeA obtained from i.v. data. Following an i.v. dose, DHE distributed into the brain with a brain-to-plasma concentration ratio of 5% at 30 min postdose. The PeA value of DHE ranged from 8.6× 10 -4 to 37.5× 10 -4 mL min -1 g -1 in different brain regions. Following i.n. doses the experimentally determined concentration in olfactory bulb was approximately 51 times, and in other regions three to seven times, greater than predicted values based only on PeA and plasma AUC, suggesting a direct transport pathway from the nasal cavity to the brain. As a result, the brain tissue concentrations at 30 min were similar to (0.31 -1.04 times) those following an i.v. dose except for the olfactory bulb, in which the concentration was approximately four times greater than that following an i.v. dose. In conclusion, 3 H-DHE penetrated the BBB following intravenous administration. Following i.n. doses, 3 H-DHE was able to enter the brain directly from the nasal cavity, with the olfactory bulb being a part of the direct passage from nasal cavity to brain.