Intranasal absorption of Delta(9)-tetrahydrocannabinol and WIN55,212-2 mesylate in rats.
The aim of this study was to examine the potential of the nasal route for systemic delivery of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and WIN55,212-2 mesylate. Anesthetized rats were surgically prepared to isolate the nasal cavity, into which Delta(9)-THC (10 mg/kg) or WIN55,212-2 (150 microg/kg) in propylene glycol alone or propylene glycol and ethanol (9:1) were administered. Rats were also administered Delta(9)-THC (1 mg/kg) and WIN55,212-2 (150 microg/kg) intravenously in order to determine absolute bioavailabilities of the nasal doses. Plasma Delta(9)-THC and WIN55,212-2 concentrations were determined by liquid chromatography/mass spectroscopy (LC/MS). The pharmacokinetics of the drugs after intranasal administration was best described by a one-compartment model with an absorption phase. WIN55,212-2 was absorbed more rapidly (T(max)=0.2-0.3h) than Delta(9)-THC (T(max)=1.5-1.6h) and to a higher extent than Delta(9)-THC. Addition of ethanol (10%) to the formulations had no significant effect on the C(max) after nasal administration (p>0.05). Furthermore, it had no significant effect on the absolute bioavailability (F(abs)): F(abs)=6.4+/-2.4% and 9.1+/-3.0% for Delta(9)-THC in propylene glycol, with and without ethanol, respectively. For WIN55,212-2, F(abs)=49.9+/-6.9% (propylene glycol alone) and 56.6+/-14.1% (propylene glycol with 10% ethanol). The results of the study showed that systemic delivery of Delta(9)-tetrahydrocannabinol and WIN55,212-2 could be achieved following nasal administration in rats.
Valiveti
Satyanarayana
S
University of Kentucky College of Pharmacy, Lexington, KY 40536, USA.
Agu
Remigius U
RU
Hammell
Dana C
DC
Paudel
Kalpana S
KS
Earles
D Caroline
DC
Wermeling
Daniel P
DP
Stinchcomb
Audra L
AL
D000042:Absorption; D000465:Algorithms; D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D048588:Benzoxazines; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D002853:Chromatography, Liquid; D013759:Dronabinol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000431:Ethanol; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D009025:Morpholines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability; D011092:Polyethylene Glycols; D019946:Propylene Glycol; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents
D000932:Antiemetics; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D009025:Morpholines; D009281:Naphthalenes; D012997:Solvents; D000431:Ethanol; D011092:Polyethylene Glycols; 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; D013759:Dronabinol