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Abstract
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BACKGROUND: Comparative bioavailability of cannabinoids following their administration by dosing routes has been studied previously, but there are no quantitative reports of distribution of Δ(9)THC, nor its metabolites, across various brain regions following intranasal (i.n.) administration. The aim of the present study was to determine the time course of Δ(9)THC transport from nose to brain and to quantify the distribution of Δ(9)THC and its metabolites in four brain regions.
METHODS: Δ(9)THC was formulated as a lipophilic nano-emulsion and instilled i.n. to three groups of adult mice and euthanized after 2, 4, and 8 h. Brains were dissected into 4 regions. Sensitive analytical methods (HPLC-MS) were utilized to quantify levels of Δ(9)THC and metabolites in brain regions and peripheral tissues. Data was expressed as mean concentrations (± SEM) of Δ(9)THC and metabolites in brain regions, blood, plasma, urine, and liver. Two-way analysis of variance was performed followed by post hoc multiple comparisons.
RESULTS: Peak concentrations of Δ(9)THC were reached at 2 h in the brain (15.9 ng/mg), blood (4.54 μg/mL), and plasma (4.56 μg /mL). The percentage of administered dose of Δ(9)THC transported to the brain (5.9%) was greater than in blood (1.7%), plasma (1.6%), urine (0.4%), and liver (0.1%). Concentrations of Δ(9)THC and its THC-COOH metabolite in the liver reached their highest levels at 8 h.
DISCUSSION: The present study is the first to report the uptake and distribution across brain regions of Δ(9)THC and its principal metabolites following i.n. administration. The systemic bioavailability (absorption into the blood) of intranasal Δ(9)THC was 1.7% of the administered dose, much lower than that reported by others after oral ingestion (7-10%) and inhalation (20-35%), but those prior studies did not measure the transport of Δ(9)THC into brain regions. Others have reported Δ(9)THC in the whole brain following i.n. instillation in a different species (rats) to be twice (5.9%) that following i.p. injections, while metabolites of Δ(9)THC in rat brain were lower after i.n. administration.
CONCLUSIONS: The intranasal route of a Δ(9)THC nanoformulation is an effective way to deliver cannabinoids to the brain, especially in those who cannot take the medication orally. Going forward, a metered dosing nasal spray will provide accurate and consistent doses.
Language: en |