title: Oral delivery of 1,3-dicyclohexylurea nanosuspension enhances exposure and lowers blood pressure in hypertensive rats.
abstract: Cytochrome P450-derived epoxyeicosatrienoic acids (EET) are biologically active metabolites of arachidonic acid that have potent effects on renal vascular reactivity and tubular ion transport and have been implicated in the control of blood pressure. EETs are hydrolyzed to their less active diols, dihydroxyeicosatrienoic acids (DHET), by the enzyme soluble epoxide hydrolase (sEH). 1,3-dicyclohexylurea (DCU), a potent sEH inhibitor, lowers systemic blood pressure in spontaneously hypertensive rats when dosed intraperitoneally. However, DCU has poor aqueous solubility, posing a challenge for in vivo oral delivery. To overcome this limitation, we formulated DCU in a nanosuspension using wet milling. Milling reduced particle size, increasing the total surface area by approximately 40-fold. In rats chronically infused with angiotensin II, the DCU nanosuspension administered orally twice daily for 4 days produced plasma exposures an order of magnitude greater than unmilled DCU and lowered blood pressure by nearly 30 mmHg. Consistent with the mechanism of sEH inhibition, DCU increased plasma 14,15-EET and decreased plasma 14,15-DHET levels. These data confirm the antihypertensive effect of sEH inhibition and demonstrate that greatly enhanced exposure of a low-solubility compound is achievable by oral delivery using a nanoparticle drug delivery system.
authors.affiliation: Pfizer Global Research and Development, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. sarbani.ghosh@pfizer.com
authors.forename: Sarbani
authors.initials: S
authors.lastname: Ghosh
authors.forename: Po-Chang
authors.initials: PC
authors.lastname: Chiang
authors.forename: Jan L
authors.initials: JL
authors.lastname: Wahlstrom
authors.forename: Hideji
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Jon G
authors.initials: JG
authors.lastname: Selbo
authors.forename: Steven L
authors.initials: SL
authors.lastname: Roberds
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013535:Suspensions; D053719:Tandem Mass Spectrometry; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D013535:Suspensions; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D014508:Urea; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; C000948:1,3-dicyclohexylurea