High levels of morphine-6-glucuronide in street heroin addicts

Rationale In the body, heroin is rapidly transformed to 6-acetylmorphine (6-AM) and then to morphine, that in turn is mainly metabolized to morphine-3-glucuronide (M3G) and, at lesser extent, to morphine-6-glucuronide (M6G). Unlike M3G, M6G is a potent opioid agonist. Intravenous heroin abusers (IHU) are exposed to a wide array of drugs and contaminants that might affect glucuronidation. Objectives We assessed plasma and urine concentrations of M3G and M6G in four groups of subjects: the first two included long-term IHU either exposed to street heroin (n=8) or receiving a single IV injection of morphine (n=4), while the other two groups included non-IHU patients receiving acute IV (n=8) or chronic oral (n=6) administrations of morphine. Methods After solid phase extraction plasma and urine concentrations of morphine metabolites were determined by HPLC analyses. Results M3G accounted for the greater part of morphine glucuronides detected in body fluids of non-IHU patients treated with morphine. This pattern of metabolism remained stable across 15 days of oral administration of incremental doses of morphine. In contrast, the two groups of IHU (street heroin taking or morphine-treated subjects) showed a reduction of blood and urine M3G concentrations in favor of M6G. Consequently, M6G/M3G ratio was significantly higher in the two IHU groups in comparison with the non-IHU groups. Conclusions Chronic exposure to street heroin causes a relative increase in concentrations of the active metabolite, M6G. Since the pattern of M6G action seems closer to heroin than to morphine, the increased synthesis of M6G observed in IHU may prolong the narrow window of heroin effects.