Δ9-THC Hemisuccinate in Suppository Form as an Alternative to Oral and Smoked THC



Although Δ9-tetrahydrocannabinol (THC) has demonstrated utility for several medicinal applications, several studies have reported the inconsistent bioavailability of the oral soft gelatin capsule formulation, because of erratic absorption and variable first-pass metabolism of THC. This problem limits the utility of THC for its approved indications, and also prevents efficient assessment of other potential therapeutic applications. In an effort to overcome these pharmacokinetic limitations, we have explored the utility of various ester prodrugs of THC in suppository formulations as alternatives for effecting the systemic delivery of THC. Studies designed to characterize the bioavailability and efficacy of these preparations are reviewed here. In addition, studies designed to confirm the behavior of THC-hemisuccinate (THC-HS) as a prodrug were conducted. In rodents and dogs, intravenous administration of THC and THC-HS produced identical pharmacological responses (hypothermia and potentiation of thiamylal sleep times in mice; bradycardia in dogs) except at very high doses. Pharmacokinetic evaluations after intravenous and rectal administration of THC-HS also showed that the parent ester could not be detected in plasma, but that THC and its metabolite were detected in a fashion consistent with the immediate hydrolysis of THC-HS to THC in the absorption process or in the plasma. Administration of the THC-HS via suppositories resulted in excellent bioavailability, sustained plasma levels of THC, and improved efficacy as compared to the oral formulations, suggesting the feasibility of this route for the delivery of THC in various therapeutic applications.


Hypothermic Effect Parent Ester Appetite Stimulation Suppository Formulation Lipophilic Base 
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