title: Pharmacokinetic interactions between ethanol and heroin: a study on post-mortem cases.
abstract: BACKGROUND
  Ethanol and heroin are both depressant drugs on the central nervous system, and combined use is known to be dangerous due to pharmacodynamic interactions, leading to an even higher risk of respiratory depression and death. In addition, previous studies have suggested a pharmacokinetic interaction between ethanol and the metabolism of heroin. The aim of the present study was to investigate if there was a pharmacokinetic interaction between heroin and ethanol, by comparing concentrations of heroin metabolites in cases with and without ethanol, as detected in blood samples collected from a large material of forensic autopsy cases.
  
  
  METHODS
  The material consisted of 1583 forensic autopsy cases, all containing 6-monoacetylmorphine (6-MAM), as evidence of heroin intake, in either blood or urine samples, from the time period between the 1st of January 2000 and the 31st of December 2012. Due to the high risk of post-mortem ethanol formation in cases revealing blood ethanol concentrations between 0.1 and 0.3‰, these cases were excluded from the study, along with cases where the analysis for ethanol was missing. After this exclusion of cases, the material (n=1474) was divided into two groups; one group where ethanol was not detected in blood (n=1160), and another group where ethanol was detected in blood at or above the concentration of 0.4‰ (n=314). Furthermore, the material was also divided into two other subgroups; one group where 6-MAM was detected in blood samples, indicating a very recent intake of heroin, and another group where 6-MAM was detected in the urine, but not in blood, indicating a less recent heroin intake.
  
  
  RESULTS
  The concentration ratios of morphine/6-MAM, morphine-3-glucuronide (M3G)/morphine, and morphine-6-glucuronide (M6G)/morphine in blood samples, were all significantly lower in the ethanol positive cases compared with that of the ethanol negative cases. For the subgroup of cases revealing a very recent intake of heroin (n=645), only the morphine/6-MAM ratio was significantly lower in the ethanol positive cases than in the ethanol negative cases. For the subgroup of cases with a less recent heroin intake (n=817), lower M3G/morphine and M6G/morphine ratios were found among the ethanol positive cases.
  
  
  CONCLUSIONS
  The results indicate that ethanol inhibits two steps in the heroin metabolism; the hydrolysis of 6-MAM to morphine, and the glucuronidation of morphine to M3G and M6G. This pharmacokinetic interaction could further complicate the outcome after combined use of heroin and ethanol, in addition to the already well-known pharmacodynamic interactions.
authors: Division of Forensic Medicine and Drug Abuse Research, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway. Electronic address: cecilie.thaulow@fhi.no.
authors: C H
authors: CH
authors: Thaulow
authors: Division of Forensic Medicine and Drug Abuse Research, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway.
authors: G
authors: G
authors: Høiseth
authors: Division of Forensic Medicine and Drug Abuse Research, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway.
authors: J M
authors: JM
authors: Andersen
authors: Division of Epidemiology, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway.
authors: M
authors: M
authors: Handal
authors: Division of Forensic Medicine and Drug Abuse Research, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway.
authors: J
authors: J
authors: Mørland
mesh_terms: D002492:Central Nervous System Depressants / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D000431:Ethanol / Q000097:blood / Q000493:pharmacokinetics*; D053593:Forensic Toxicology; D003932:Heroin / Q000032:analysis / Q000493:pharmacokinetics*; D006801:Humans; D009022:Morphine Derivatives / Q000032:analysis; D009294:Narcotics / Q000032:analysis / Q000493:pharmacokinetics*
chemical_list: D002492:Central Nervous System Depressants; D009022:Morphine Derivatives; D009294:Narcotics; D000431:Ethanol; C035349:morphine-6-glucuronide; D003932:Heroin; C026979:6-O-monoacetylmorphine; C018108:morphine-3-glucuronide
keywords: Ethanol; Heroin; Metabolism; Pharmacokinetic interactions; Post-mortem