The Effect of Route of Administration and Vehicle on the Pharmacokinetics of THC and CBD in Adult, Neonate, and Breastfed Sprague-Dawley Rats.

Abstract

Introduction: Basic pharmacokinetic (PK) and pharmacodynamic models of the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are critical for developing translational models of exposure and toxicity. The neonatal period is a particularly important time to study the effects of cannabinoids, yet there are few studies of cannabinoid PKs by different routes such as direct injection or breast milk ingestion. To study this question, we have developed a translationally relevant rodent model of perinatal cannabinoid administration by measuring plasma levels of THC and CBD after different routes and preparations of these drugs. Materials and Methods: Adult animals and pups were injected with THC or CBD either intraperitoneally or subcutaneously, and plasma was analyzed by liquid chromatography-tandem mass spectrometry to measure cannabinoid levels collected at specified intervals. We also tested the effect of preparation of the drug using an oil-based vehicle (sesame oil) and an aqueous vehicle (Tween). Finally, we measured the plasma levels of cannabinoids in neonatal pups that were transmitted through breast milk after intraperitoneal injection to nursing dams. Results: We observed differences in the PK profiles of cannabinoids in adults and neonatal pups that were dependent on the route of administration and type of vehicle. Cannabinoids prepared in aqueous vehicle, injected intraperitoneally, resulted in a high peak in plasma concentration, which rapidly decreased. In contrast, subcutaneous injections using sesame oil as a vehicle resulted in a slow rise and low plateau in plasma concentration. Intraperitoneal injections with sesame oil as a vehicle resulted in a slower rise compared with aqueous vehicle, but an earlier and higher peak compared with subcutaneous injection. Finally, the levels of THC and CBD that were similar to direct subcutaneous injections were measured in the plasma of pups nursing from intraperitoneally injected dams. Conclusions: The route of administration and the preparation of the drug have important and significant effects on the PK profiles of THC and CBD in rats. These results can be used to create different clinically relevant exposure paradigms in pups and adults, such as short high-dose exposure or a low-chronic exposure, each of which might have significant and varying effects on development.