Pharmacokinetics of Cannabidiol in Sprague-Dawley Rats After Oral and Pulmonary Administration

Introduction: Cannabidiol (CBD) is primarily consumed through ingestion and inhalation. Little is known about how CBD pharmacokinetics differ between routes of administration, and duration of pulmonary exposure. Methods: Pharmacokinetics, brain distribution, and urinary elimination of CBD and its major metabolites (6-hydroxy-cannabidiol [6-OH-CBD], 7-hydroxy-cannabidiol [7-OH-CBD], 7-carboxy-cannabidiol [7-COOH-CBD], and CBD-glucuronide) were evaluated in adult Sprague-Dawley rats following a single oral CBD ingestion (10 mg/kg in medium chain triglyceride oil; 24 male animals), and 1 or 14 days of repeated inhalation (0.9-13.9 mg/kg in propylene glycol [41%/59% by weight]; 5 male and 5 female animals per dose). Blood and brain tissue were collected at a single time point from each animal. Collection times were staggered from 5 min to 24 h postoral gavage or first (blood only) and final inhalation. Urine was collected 24 h postoral gavage or final inhalation. Samples were analyzed through liquid chromatography-mass spectrometry (LC-MS/MS). Results: CBD was more rapidly absorbed following inhalation than ingestion (T_max=5 min and 2 h, respectively). Inhalation resulted in a dose-responsive increase in CBD C_max and AUC_last. CBD C_max was 24-fold higher following the highest pulmonary dose (13.9 mg/kg) versus an oral dose of comparable concentration (10 mg/kg). C_max and AUC_last (0-16 h) trended higher following repeated exposure. Elimination was notably faster with repeated CBD inhalation (t_1/2=5.3 and 2.4 h on days 1 and 14, respectively). While metabolites were detectable in plasma, AUC_last (0-2 h) was at least 10- (7-OH-CBD, 7-COOH-CBD) to 100- (6-OH-CBD) fold lower than the parent compound. Metabolite concentration trended higher following repeated inhalation (6.7 mg/kg CBD); AUC_last (0-16 h) was ∼1.8-, ∼1.4-, and ∼2.4-fold higher following 14 days of exposure for 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, respectively. CBD was detectable in brain homogenate tissue 24-h after 14-day inhalation (>3.5 mg/kg deposited dose) or a single oral administration. CBD metabolites were only measurable in brain tissue following the highest inhaled dose (13.9 mg/kg CBD). CBD, but not metabolites, was detectable in urine for all dose groups following 2 weeks of CBD inhalation. Neither CBD nor metabolites were present in urine after oral administration. Conclusion: CBD pharmacokinetics differ across oral and pulmonary routes of administration and acute or repeated dosing.