Levels of heroin and its metabolites in blood and brain extracellular fluid after i.v. heroin administration to freely moving rats

Br J Pharmacol. 2013 Oct;170(3):546-56. doi: 10.1111/bph.12305.


Background and purpose: Heroin, with low affinity for μ-opioid receptors, has been considered to act as a prodrug. In order to study the pharmacokinetics of heroin and its active metabolites after i.v. administration, we gave a bolus injection of heroin to rats and measured the concentration of heroin and its metabolites in blood and brain extracellular fluid (ECF).

Experimental approach: After an i.v. bolus injection of heroin to freely moving Sprague-Dawley rats, the concentrations of heroin and metabolites in blood samples from the vena jugularis and in microdialysis samples from striatal brain ECF were measured by ultraperformance LC-MS/MS.

Key results: Heroin levels decreased very fast, both in blood and brain ECF, and could not be detected after 18 and 10 min respectively. 6-Monoacetylmorphine (6-MAM) increased very rapidly, reaching its maximal concentrations after 2.0 and 4.3 min, respectively, and falling thereafter. Morphine increased very slowly, reaching its maximal levels, which were six times lower than the highest 6-MAM concentrations, after 12.6 and 21.3 min, with a very slow decline during the rest of the experiment and only surpassing 6-MAM levels at least 30 min after injection.

Conclusions and implications: After an i.v. heroin injection, 6-MAM was the predominant opioid present shortly after injection and during the first 30 min, not only in the blood but also in rat brain ECF. 6-MAM might therefore mediate most of the effects observed shortly after heroin intake, and this finding questions the general assumption that morphine is the main and most important metabolite of heroin.

Keywords: CNS; acetylmorphine; distribution; heroin; metabolite kinetic; microdialysis; morphine; opioid; pharmacokinetic; prodrug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Biotransformation
  • Brain / metabolism*
  • Chromatography, Liquid
  • Extracellular Fluid / metabolism*
  • Heroin / administration & dosage*
  • Heroin / blood*
  • Heroin / pharmacokinetics*
  • Male
  • Morphine Derivatives / blood
  • Motor Activity*
  • Rats
  • Rats, Sprague-Dawley
  • Tandem Mass Spectrometry


  • Analgesics, Opioid
  • Morphine Derivatives
  • Heroin
  • 6-O-monoacetylmorphine