Wang Y, Aun R, Tse F L
Drug Metabolism and Pharmacokinetics Department, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Biopharm Drug Dispos. 1998 Dec;19(9):571-5. doi: 10.1002/(sici)1099-081x(199812)19:9<571::aid-bdd142>3.0.co;2-o.
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 (3H-DHE) with 14C-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 permeability*area product (PeA) following an i.v. dose was calculated based on the 30-min brain tissue concentration and the area under the plasma concentration-time curve (AUC0-30 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 AUC0-30 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 approximately 5% at 30 min postdose. The PeA value of DHE ranged from 8.6 x 10(-4) to 37.5 x 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, 3H-DHE penetrated the BBB following intravenous administration. Following i.n. doses, 3H-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.
本研究旨在确定大鼠静脉注射和鼻内给药后二氢麦角胺（DHE）在脑中的摄取情况。八只麻醉大鼠接受静脉注射（i.v.）或连续两次鼻内（i.n.）给予氚标记的二氢麦角胺（3H-DHE），同时给予14C-菊粉作为非血脑屏障（BBB）通透性标记物。给药后30分钟内的指定时间测定血浆中的放射性浓度，并在30分钟时测定血液和七个脑区（嗅球、额叶皮质、顶叶皮质、枕叶皮质、小脑、中脑区域和脑干）中的放射性浓度。静脉注射剂量后的血浆-脑通透性*面积乘积（PeA）根据30分钟时的脑组织浓度和血浆浓度-时间曲线下面积（AUC0-30分钟，i.v.）计算，假设从血浆到脑的单向转运。基于实验测定的脑中放射性量评估从鼻腔到脑的直接转运，并根据血浆AUC0-30分钟，i.n.和从静脉注射数据获得的PeA进行预测。静脉注射剂量后，DHE在给药后30分钟时以约5%的脑-血浆浓度比分布到脑中。DHE在不同脑区的PeA值范围为8.6×10（-4）至37.5×10（-4）mL min（-1）g（-1）。鼻内给药后，嗅球中实验测定的浓度约为仅基于PeA和血浆AUC预测值的51倍，其他区域为三至七倍，表明存在从鼻腔到脑的直接转运途径。因此，除嗅球外，30分钟时的脑组织浓度与静脉注射剂量后的浓度相似（0.31-1.04倍），嗅球中的浓度约为静脉注射剂量后浓度的四倍。总之，静脉注射后3H-DHE穿透了血脑屏障。鼻内给药后，3H-DHE能够直接从鼻腔进入脑内，嗅球是从鼻腔到脑的直接通道的一部分。
