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

Abstract

BACKGROUND AND PURPOSEHeroin, 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 APPROACHAfter 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 RESULTSHeroin 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 IMPLICATIONSAfter 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. Abbreviations6-MAM, 6-monoacetylmorphine; AUCLast, area under the concentration-time curve from time zero to last sample time; Cmax, maximum concentration; BBB, blood-brain barrier; Cl, clearance; Cu, concentration of unbound analyte in brain

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

“…Previous work in our laboratory has shown that 6-MAM is the predominating metabolite in brain and blood after subcutaneous and intravenous heroin administration in mice and rats, respectively, indicating that 6-MAM is the main contributor to acute heroin effects Gottås et al, 2013). In addition, the psychomotor-stimulating effect and dopamine peak levels coincided with the rising concentration of 6-MAM in brain tissue, at a time when heroin was no longer detectable Gottås et al, 2013Gottås et al, , 2014. Furthermore, pharmacokinetic studies have indicated that heroin is mainly metabolized outside the brain .…”

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

“…Extrapolation of rat data to humans is made more difficult for heroin because the main active components are its metabolites 6-AM and morphine. These metabolites are formed at different rates in humans compared with rodents (Comer et al, 1999;Rentsch et al, 2001;Gottås et al, 2013) and their rates of distribution to brain may also differ. These considerations underscore the need to advance opioid vaccines to human studies to properly assess their therapeutic potential.…”

The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis

“…Drug exposure can be measured using an animal model by microdialysis at the target site (Gottås et al, 2013). Because the dialysate contained a considerable amount of nonvolatile salts, the ionization of analytes would be suppressed when microdialysate was directly analyzed by UPLC-MS/MS without prior sample preparation.…”

“…Simultaneous monitoring of brain monoamine level changes by the in vivo microdialysis sampling technique is an important tool in the discovery of new drug therapies for a large number of neurologic disorders, such as Parkinson's disease, Alzheimer's disease, epilepsy, and neuropsychiatric disorders (Garrison et al, 2002). The advantages of the microdialysis technique include not only simultaneous sampling at multiple sites, such as the brain (Gottås et al, 2013), but also that there is no need for sample preparation because the dialysis membrane excludes proteins from the aqueous sample (Tsai, 2003). The use of ionpair high-performance liquid chromatography-electrochemical detection (HPLC-ECD) is of great interest for the determination of monoamine neurotransmitters [i.e., norepinephrine; epinephrine; 3,4-dihydroxyphenylacetic acid (DOPAC); DA; 5-hydroxyindole-3-acetic acid (5-HIAA); homovanillic acid (HVA); 5-HT; and 3-methoxytyramine hydrochloride] in microdialysis samples (Bicker et al, 2013).…”