Heroin metabolism in human blood and its impact for the design of an immunotherapeutic approach against heroin effects

Immunotherapeutic interventions that block drug effects by binding drug molecules to specific antibodies in the bloodstream have shown promising effects in animal studies. For heroin, which effects are mainly mediated by the metabolites 6-acetylmorphine (6-AM; also known as 6-monoacetylmorphine or 6-MAM) and morphine, the optimal antibody specificity has been discussed. In rodents, 6-AM specific antibodies have been recommended based on the rapid metabolism of heroin to 6-AM in the bloodstream. Since the metabolic rate of heroin in blood is unsettled in humans, we examined heroin metabolism with state-of-the-art analytical methodology (UHPLC-MS/MS) in freshly drawn human whole blood incubated with a wide range of heroin concentrations (1-500 & mu;M). The half-life of heroin was highly concentration dependent, ranging from 1.2-1.7 min for concentrations at or above 25 & mu;M, and gradually increasing to approximately 20 min for 1 & mu;M heroin. At concentrations that can be attained in the bloodstream shortly after an i.v. injection, approximately 70% was transformed into 6-AM within 3 min, similar to previous observations in vivo. Our results indicate that blood enzymes play a more important role for the rapid metabolism of heroin in humans than previously assumed. This points to 6-AM as an important target for an efficient immunotherapeutic approach to block heroin effects in humans.