In vitro stability of cannabinergic prodrugs in plasma
Pham, Andrew C
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The endocannabinoid system has been a promising target for novel drug therapies, especially because of its role in alleviating neuropathic pain. Recent drug development has been geared to specifically target CB2 receptors to inhibit neuropathic pain without the psychotropic side effects associated with CB1 agonism. There have been problems developing oral formulations of CB2-specific cannabinergic drugs because of their low bioavailability. This issue can be addressed by creating prodrugs of these compounds with enhanced bioavailability. This study evaluates the in vitro half lives of monofunctional and bifunctional esteratic prodrug structures of two CB2-targeted cannabinergic drugs. These prodrug formulations have one or two ester bonds that must be hydrolyzed before the active drug is released. The prodrugs and active products were incubated in human, mouse, and rat plasma, as well as non-enzyme containing buffers, and concentrations were measured over time by HPLC. The active drug products were stable in all solutions. The prodrugs were found to have in vitro half lives in human plasma ranging from 2.50 to 6950 minutes and exhibited accelerated degradation in mouse and rat plasma for the majority of compounds. Non-enzymatic hydrolysis was observed in TME buffer for many of these compounds, but at a much slower rate than in the enzyme-containing plasma. Further in vivo pharmacokinetic research with these compounds will be required to evaluate their oral bioavailability and efficacy for affecting the endocannabinoid system.
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