Measurement of Δ9THC and metabolites in the brain and peripheral tissues after intranasal instillation of a nanoformulation.

Abstract

Background: Comparative bioavailability of cannabinoids following their administration by dosing routes has been studied previously, but there are no quantitative reports of distribution of Δ⁹THC, 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 Δ⁹THC transport from nose to brain and to quantify the distribution of Δ⁹THC and its metabolites in four brain regions.

Methods: Δ⁹THC 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 Δ⁹THC and metabolites in brain regions and peripheral tissues. Data was expressed as mean concentrations (± SEM) of Δ⁹THC 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 Δ⁹THC 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 Δ⁹THC 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 Δ⁹THC 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 Δ⁹THC and its principal metabolites following i.n. administration. The systemic bioavailability (absorption into the blood) of intranasal Δ⁹THC 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 Δ⁹THC into brain regions. Others have reported Δ⁹THC 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 Δ⁹THC in rat brain were lower after i.n. administration.

Conclusions: The intranasal route of a Δ⁹THC 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.