Category: Professional Posters
Purpose: Heroin is involved in more than one third of opioid-related overdose deaths in the US and is derived from morphine. Upon administration, heroin is primarily and rapidly deacetylated to form the active metabolites 6-monoacetylmorphine (6-MAM) and morphine. Studies have indicated that a delay of heroin hydrolysis in plasma can lead to increased 6-MAM and morphine exposure in the brain, and thereby increased drug effects. In this study, we assessed the contribution of the major hepatic hydrolase, carboxylesterase 1 (CES1), to heroin metabolism and evaluated the potential influence of known CES1 inhibitors on the hydrolysis of the drug in the liver.
Methods: In vitro systems using S9 fractions from either human liver or human embroynic kidney 293 cells stably expressing wild-type CES1 were employed in our assessment. Depletion of heroin and formation of 6-MAM and morphine were monitored by LC-MS/MS. Kinetic parameters were derived from nonlinear regression analysis.
Results: Under our experimental conditions, 6-MAM was formed by both liver and cell S9, while morphine was only formed by liver S9. By employing the relative activity factor approach, the contribution of CES1 to the first-step hydrolysis of heroin in the liver was determined as 4.35%. Co-incubation with CES1 selective inhibitor valproic acid had limited effects on heroin metabolism. The major cannabinoids (∆9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN)), exhibited potent in vitro inhibition on both 6-MAM and morphine formation at 5 µg/ml, but had insignificant influence at their physiological concentrations.
Conclusion: These results suggest positive, although limited involvement of CES1 in the conversion of heroin into 6-MAM in the liver. Due to its limited contribution, drugs with known activity-modifying effects toward CES1 are not expected to cause significant influence on heroin disposition. Cannabinoids, which have recently been proposed to fight opioid addictions, may have the potential to interact with heroin and thereby should be used with cautions for this purpose.