Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system.
The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS). Intranasal delivery is a noninvasive method that targets drugs to the brain and spinal cord along olfactory and trigeminal neural pathways, bypassing the BBB and minimizing systemic exposure and side effects. To assess intranasal drug targeting of a neuropeptide (hypocretin-1, HC) to the CNS, pharmacokinetics in blood, CNS tissues, and peripheral tissues were compared after intranasal and intravenous infusion to anesthetized rats. Despite a 10-fold lower blood concentration of HC with intranasal administration, both routes resulted in similar brain concentrations. Tissue-to-blood concentration ratios after intranasal administration were significantly greater in all brain regions over 2 h compared to intravenous administration, with the highest ratios in the trigeminal nerve (14-fold) and olfactory bulbs (9-fold). Intranasal delivery increased drug targeting to the brain and spinal cord 5- to 8-fold. Approximately 80% of the area under the brain concentration-time curve following intranasal administration was due to direct transport from the nasal passages. Intranasal delivery rapidly targets HC to the CNS with minimal systemic exposure, most of which reaches the brain intact by mechanisms not involving distribution from the blood and/or cerebrospinal fluid.
Dhuria
Shyeilla V
SV
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Hanson
Leah R
LR
Frey
William H
WH
D000281:Administration, Intranasal; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D004355:Drug Stability; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D009479:Neuropeptides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D018377:Neurotransmitter Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins