Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts

Girardin, François

doi:10.1016/s0009-9236(03)00199-1

Cited by 50 publications

(46 citation statements)

References 14 publications

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“…Because IgG has two binding sites per antibody molecule, 1-10 mM drug-binding sites were available. This is within a clinical relevant concentration range as C max of 6-MAM has been measured to be 5.0-17.5 mM after intravenous injection of heroin in heroin users (Rentsch et al, 2001;Girardin et al, 2003;Rook et al, 2006b). One of the advantages of passive immunization is the possibility to easily increase the antibody levels in the blood by giving higher doses of antidrug mAb.…”

Section: Controlmentioning

confidence: 64%

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

Bogen¹,

Boix²,

Nerem³

et al. 2014

J Pharmacol Exp Ther

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Immunotherapy against drugs of abuse is being studied as an alternative treatment option in addiction medicine and is based on antibodies sequestering the drug in the bloodstream and blocking its entry into the brain. Producing an efficient vaccine against heroin has been considered particularly challenging because of the rapid metabolism of heroin to multiple psychoactive molecules. We have previously reported that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the predominant mediator for heroin's acute behavioral effects and that heroin is metabolized to 6-MAM primarily prior to brain entry. On this basis, we hypothesized that antibody sequestration of 6-MAM is sufficient to impair heroin-induced effects and therefore examined the effects of a monoclonal antibody (mAb) specific for 6-MAM. In vitro experiments in human and rat blood revealed that the antibody was able to bind 6-MAM and block the metabolism to morphine almost completely, whereas the conversion of heroin to 6-MAM remained unaffected. Mice pretreated with the mAb toward 6-MAM displayed a reduction in heroin-induced locomotor activity that corresponded closely to the reduction in brain 6-MAM levels. Intraperitoneal and intravenous administration of the anti-6-MAM mAb gave equivalent protection against heroin effects, and the mAb was estimated to have a functional half-life of 8 to 9 days in mice. Our study implies that an antibody against 6-MAM is effective in counteracting heroin effects.

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Section: Controlmentioning

confidence: 64%

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

Bogen¹,

Boix²,

Nerem³

et al. 2014

J Pharmacol Exp Ther

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“…These preclinical data contrast with several human studies that found heroin to be the predominant opioid in plasma shortly (2 to 10 minutes) after similar i.v. doses of heroin (Comer et al, 1999;Girardin et al, 2003). The metabolism of heroin to 6-MAM and morphine in plasma is attributable to esterases in blood as well as non-enzymatic degradation (Salmon et al, 1999;Selley et al, 2001;Rook et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

Raleigh

Pravetoni

Harris

et al. 2012

J Pharmacol Exp Ther

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Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines.

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“…However, many patients must receive prescribed diacetylmorphine orally rather than intravenously due to venosclerosis [10]. We therefore studied the kinetics of diacetylmorphine and its metabolites such as morphine after oral diacetylmorphine in opioid-dependent patients [11] and found that oral diacetylmorphine, up to doses of 600 mg, led to only negligible systemic diacetylmorphine and monoacetylmorphine concentrations. However, our study in opioid-dependent patients showed for the first time that high doses of oral diacetylmorphine, considered as a morphine prodrug, lead to unexpectedly high morphine bioavailabilities of 64, 66 and 72% for average doses of 206, 413 and 619 mg, respectively.…”

Section: Introductionmentioning

confidence: 99%

Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

Halbsguth

Rentsch

Eich-Höchli

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Venosclerosis prevents many opioid addicts in heroin substitution programmes from injecting intravenously, which makes consideration of other routes of administration necessary. • Even high doses of oral diacetylmorphine are completely converted to morphine presystemically. • Morphine bioavailability in heroin addicts after high‐dose oral diacetylmorphine administration is considerably higher than expected based on prior data obtained with relatively low oral diacetylmorphine or morphine doses in healthy subjects or patients receiving treatment for pain (64–72% vs. 20–25%). WHAT THIS STUDY ADDS • Morphine influx into systemic circulation is more rapid after oral diacetylmorphine than after oral morphine, resulting in earlier and more than double maximal concentrations. • In opioid‐dependent people, bioavailability of morphine from oral doses of diacetylmorphine is also 37% higher than that of oral morphine. • Morphine bioavailability is two and 1.5 times higher in chronic users than in opioid‐naive subjects after low oral doses of diacetylmorphine or morphine, respectively. • Oral absorption of morphine from diacetylmorphine is dose dependent, i.e. bioavailability increases with diacetylmorphine dose. AIMS In the Swiss heroin substitution trials, patients are treated with self‐administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high‐dose oral diacetylmorphine is considerably higher than would be predicted from low‐dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose. METHODS Opioid‐naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium‐labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose. RESULTS The maximum plasma concentration (Cmax) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 µmol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 µmol). CONCLUSIONS Oral absorption of opioids is substance‐, dose‐ and patient collective‐dependent, suggesting that there may be a saturation of first‐pass processes, th...

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Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts

Cited by 50 publications

References 14 publications

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

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