Methods for Improving Drug Delivery to the Central Nervous System


The invention relates to the uses of the tricyclic antidepressant amitriptyline, its bioactive metabolites, and other LPA1R activators to improve the bioavailability and delivery of therapeutics to the central nervous system. This invention demonstrates that amitriptyline and other agents selectively decrease P-glycoprotein (P-gp) transport activity by ligand activation of lysophosphatidic acid 1 receptor (LPA1R) at the blood-brain barrier. P-gp is an effective target for increasing drug delivery to the brain (CNS) for two major reasons: (1) its substrates include a large portion of on-the-market drugs, including chemotherapeutics, and (2) its directionality results in a net efflux of drugs from the brain. Additionally, specifically targeting P-gp through LPA1R activation bypasses the clinical challenges resulting from the toxicity of substrate inhibitors of P-gp. This invention describes the inhibition of drug efflux by P-gp transport; thus, co-administration of therapeutics with amitriptyline and other LPA1R activators provides a method for increasing drug delivery to the CNS, and improving overall drug efficacy. Moreover, drug delivery to other barrier tissues will also be enhanced where a similar LPA1R-P-gp activity relationship exists.

Potential Commercial Applications: Competitive Advantages:
  • Drug delivery to the CNS
  • Co-administration of therapeutics
  • Blood-brain-barrier permeability
 


Inventors:

Ronald Cannon (NIEHS)  ➽ more inventions...

David Banks (NIEHS)  ➽ more inventions...


Intellectual Property:
US Application No. 62/453,718
US Application No. 62/332,888
PCT Application No. PCT/US2017/031206

Publications:
Chan GN, et al. PMID 28011392
Mesev EV, et al. PMID 28119480
More VR, et al. PMID 27193034
Miller DS, Cannon RE. PMID 23789954
Cartwright TA, et al. PMID 23168528

Licensing Contact:
Michael Shmilovich, J.D.
Email: shmilovm@mail.nih.gov
Phone: 301-435-5019

OTT Reference No: E-179-2016-0
Updated: Apr 18, 2018