title: Permeation of WIN 55,212-2, a potent cannabinoid receptor agonist, across human tracheo-bronchial tissue in vitro and rat nasal epithelium in vivo.
abstract: The aim of this study was to investigate the intranasal absorption of R-(+)-WIN 55,212-2 mesylate in vivo and in vitro. Permeation experiments of R-(+)-WIN 55,212-2 formulations with 2% dimethyl-beta-cyclodextrin (DMbetaCD), 2% trimethyl-beta-cyclodextrin (TMbetaCD) or 2% randomly methylated-beta-cyclodextrin (RAMbetaCD) in 1:1 propylene glycol/saline and 1.5% propylene glycol +3% Tween 80 in saline were conducted using EpiAirway tissue and an anesthetized rat nasal absorption model, respectively. Samples were analysed by liquid chromatography-mass spectrometry. Mucosal tolerance was screened using paracellular marker permeation and tissue viability as indices. Nasal absorption of WIN 55,212-2 was rapid, with a t(max) (time of peak concentration) of 0.17 to 0.35 h in vivo. Relative to 1.5% propylene glycol +3% Tween 80 (control), 1:1 propylene glycol/saline, RAMbetaCD, DMbetaCD and TMbetaCD resulted in 24-, 20-, 17- and 10-fold WIN 55,212-2 permeation increases in vitro, respectively. The in vivo absolute bioavailabilities were also increased with 1:1 propylene glycol/saline, RAMbetaCD, DMbetaCD and TMbetaCD compared to 1.5% propylene glycol +3% Tween 80 (0.15 vs. 0.66-0.77). The viability of the EpiAirway tissues was significantly reduced by DMbetaCD and TMbetaCD formulations. This study showed that WIN 55,212-2 mesylate can be delivered via the nasal route. Absorption of R-(+)-WIN 55,212-2 was rapid and bioavailability was significantly improved using methylated cyclodextrins and propylene glycol-based cosolvent.
authors.affiliation: University of Kentucky College of Pharmacy, Lexington, KY 40536-0082, USA.
authors.forename: Remigius U
authors.initials: RU
authors.lastname: Agu
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Valiveti
authors.forename: Kalpana S
authors.initials: KS
authors.lastname: Paudel
authors.forename: Mitch
authors.initials: M
authors.lastname: Klausner
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hayden
authors.forename: Audra L
authors.initials: AL
authors.lastname: Stinchcomb
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D048588:Benzoxazines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D063386:Cannabinoid Receptor Agonists; D018929:Cell Culture Techniques; D003505:Cyclodextrins / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D009831:Olfactory Mucosa / Q000166:cytology / Q000378:metabolism; D010539:Permeability; D019946:Propylene Glycol / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014132:Trachea / Q000166:cytology / Q000378:metabolism*
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D003505:Cyclodextrins; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D019946:Propylene Glycol