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Population Pharmacokinetics of Heroin and its Major Metabolites

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Abstract

Background

In several European countries and in Canada, clinical trials are being conducted in which heroin-addicted patients are treated with pharmaceutically prepared heroin in order to reduce the destructive behaviour that is so often associated with this drug.

Objective

To develop an integrated population pharmacokinetic model for heroin (diamorphine) and its pharmacodynamically active metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. Additionally, the influence on heroin pharmacokinetics of several covariates that are typical for this population was determined.

Method

Plasma concentration data from 106 heroin-dependent patients in The Netherlands (74 heroin inhalers and 32 injectors) were obtained. The ‘chasing the dragon’ technique was used for inhalation, in which the fumes of heroin base, heated on aluminum foil, were inhaled. Heroin doses varied between 66 and 450mg. Heroin, 6-acetylmorphine and morphine data were fitted simultaneously using sequential two-compartment models. Morphine-3-glucuronide and morphine-6-glucuronide data were fitted separately to one-compartment models. All data analysis was performed using nonlinear mixed-effect modelling.

Results

The bioavailability of inhaled heroin was estimated to be 53% (95% CI 43.7, 62.3). The terminal half-lives of heroin and 6-acetylmorphine were estimated to be 7.6 and 21.8 minutes, respectively. The clearances of morphine and the morphine-glucuronides were estimated to be 73.6 L/h (95% CI 62.8, 84.4) and between 6 and 10 L/h, respectively. The terminal half-life of 6-acetylmorphine was 13% lower in cocaine users (p < 0.05). No other significant relationships between covariates and pharmacokinetic parameters were discovered.

Conclusions

Pharmacokinetic parameters of heroin and its five major metabolites were assessed simultaneously in one integrated model. Covariate analyses revealed that sex, bodyweight, benzodiazepine use and creatinine clearance (>60 mL/min) do not need to be taken into account in the medical prescription of pharmaceutically prepared heroin for the treatment of heroin dependency.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Cornford EM, Braun LD, Oldendorf WH, et al. Comparison of lipid-mediated blood-brain-barrier penetrability in neonates and adults. Am J Physiol 1982; 243: C161–8

    PubMed  CAS  Google Scholar 

  2. Oldendorf WH, Hyman S, Braun L, et al. Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science 1972; 178: 984–6

    Article  PubMed  CAS  Google Scholar 

  3. Selley DE, Cao CC, Sexton T, et al. μ-Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine. Biochem Pharmacol 2001; 62: 447–55

    Article  PubMed  CAS  Google Scholar 

  4. Inturrisi CE, Schultz M, Shin S, et al. Evidence from opiate binding studies that heroin acts through its metabolites. Life Sci 1983; 33 Suppl. 1: 773–6

    Article  PubMed  CAS  Google Scholar 

  5. van den Brink W, Hendriks VM, Van Ree JM. Medical coprescription of heroin to chronic treatment resistant methadone patients in The Netherlands. J Drug Issues 1999; 29: 587–608

    Google Scholar 

  6. Perneger TV, Giner F, del Rio M, et al. Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments. BMJ 1998; 317: 13–8

    Article  PubMed  CAS  Google Scholar 

  7. van den Brink W, Hendriks VM, Blanken P, et al. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ 2003; 327: 310–5

    Article  PubMed  Google Scholar 

  8. Fischer B, Rehm J, Kirst M, et al. Heroin-assisted treatment as a response to the public health problem of opiate dependence. Eur J Public Health 2002; 12: 228–34

    Article  PubMed  Google Scholar 

  9. van Ameijden EJ, Coutinho RA. Large decline in injecting drug use in Amsterdam, 1986–1998: explanatory mechanisms and determinants of injecting transitions. J Epidemiol Community Health 2001; 55: 356–63

    Article  PubMed  Google Scholar 

  10. Hartgers C, Van den Hoek A, Krijnen P, et al. Changes over time in heroin and cocaine use among injecting drug users in Amsterdam, The Netherlands, 1985–1989. Br J Addict 1991; 86: 1091–7

    Article  PubMed  CAS  Google Scholar 

  11. Strang J, Griffiths P, Gossop M. Heroin smoking by ‘chasing the dragon’: origins and history. Addiction 1997; 92: 673–83

    Article  PubMed  CAS  Google Scholar 

  12. Skopp G, Ganssmann B, Cone EJ, et al. Plasma concentrations of heroin and morphine-related metabolites after intranasal and intramuscular administration. J Anal Toxicol 1997; 21: 105–11

    PubMed  CAS  Google Scholar 

  13. Cone EJ, Holicky BA, Grant TM, et al. Pharmacokinetics and pharmacodynamics of intranasal ’snorted’ heroin. J Anal Toxicol 1993; 17: 327–37

    PubMed  CAS  Google Scholar 

  14. Girardin F, Rentsch KM, Schwab MA, et al. Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts. Clin Pharmacol Ther 2003; 74: 341–52

    Article  PubMed  CAS  Google Scholar 

  15. Gyr E, Brenneisen R, Bourquin D, et al. Pharmacodynamics and pharmacokinetics of intravenously, orally and rectally administered diacetylmorphine in opioid dependents, a two-patient pilot study within a heroin-assisted treatment program. Int J Clin Pharmacol Ther 2000; 38: 486–91

    PubMed  CAS  Google Scholar 

  16. Jenkins AJ, Keenan RM, Henningfield JE, et al. Pharmacokinetics and pharmacodynamics of smoked heroin. J Anal Toxicol 1994; 18: 317–30

    PubMed  CAS  Google Scholar 

  17. Rentsch KM, Kullak-Ublick GA, Reichel C, et al. Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics. Clin Pharmacol Ther 2001; 70: 237–46

    Article  PubMed  CAS  Google Scholar 

  18. Santolaria-Fernandez FJ, Gomez-Sirvent JL, Gonzalez-Reimers CE, et al. Nutritional assessment of drug addicts. Drug Alcohol Depend 1995; 38: 11–8

    Article  PubMed  CAS  Google Scholar 

  19. Piccolo P, Borg L, Lin A, et al. Hepatitis C virus and human immunodeficiency virus-1 co-infection in former heroin addicts in methadone maintenance treatment. J Addict Dis 2002; 21: 55–66

    Article  PubMed  Google Scholar 

  20. de Araujo MS, Guerret S, Gerard F, et al. Quantitative studies on liver fibrosis and alpha-smooth muscle actin expression in heroin abusers. Cell Mol Biol (Noisy-le-grand) 1997; 43: 589–96

    Google Scholar 

  21. Dettmeyer RB, Preuss J, Wollersen H, et al. Heroin-associated nephropathy. Expert Opin Drug Saf 2005; 4: 19–28

    Article  PubMed  CAS  Google Scholar 

  22. do Sameiro FM, Sampaio S, Faria V, et al. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18: 2308–13

    Article  Google Scholar 

  23. Brenneisen R, Hasler F, Wursch D. Acetylcodeine as a urinary marker to differentiate the use of street heroin and pharmaceutical heroin. J Anal Toxicol 2002; 26: 561–6

    PubMed  CAS  Google Scholar 

  24. Klous MG, Nuijen B, van den BW, et al. Pharmaceutical development of an intravenous dosage form of diacetylmorphine hydrochloride. PDA J Pharm Sci Technol 2004; 58: 287–95

    PubMed  CAS  Google Scholar 

  25. Klous MG, Nuijen B, van den Brink W, et al. Development and manufacture of diacetylmorphine/caffeine sachets for inhalation via ‘chasing the dragon’ by heroin addicts. Drug Dev Ind Pharm 2004; 30: 775–84

    Article  PubMed  CAS  Google Scholar 

  26. Huizer H. Analytical studies on illicit heroin: V. Efficacy of volatilization during heroin smoking. Pharm Weekbl Sci 1987; 9: 203–11

    Article  PubMed  CAS  Google Scholar 

  27. Rook EJ, Hillebrand MJX, Rosing H, et al. The quantitative analysis of heroin, methadone and their metabolites and the simultaneous detection of cocaine, acetylcodeine and their metabolites in human plasma by high-performance liquid chromatography coupled with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 824: 213–21

    Article  PubMed  CAS  Google Scholar 

  28. Brenneisen R, Hasler F. GC/MS determination of pyrolysis products from diacetylmorphine and adulterants of street heroin samples. J Forensic Sci 2002; 47: 885–8

    PubMed  CAS  Google Scholar 

  29. Yeh SY, Gorodetzky CW, McQuinn RL. Urinary excretion of heroin and its metabolites in man. J Pharmacol Exp Ther 1976; 196: 249–56

    PubMed  CAS  Google Scholar 

  30. Elliott HW, Parker KD, Wright JA, et al. Actions and metabolism of heroin administered by continuous intravenous infusion to man. Clin Pharmacol Ther 1971; 12: 806–14

    PubMed  CAS  Google Scholar 

  31. Faura CC, Collins SL, Moore RA, et al. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998; 74: 43–53

    Article  PubMed  CAS  Google Scholar 

  32. Meineke I, Freudenthaler S, Hofmann U, et al. Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Clin Pharmacol 2002; 54: 592–603

    Article  PubMed  CAS  Google Scholar 

  33. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000; 27: 524–8

    Article  PubMed  CAS  Google Scholar 

  34. Rook EJ, Huitema ADR, Van den Brink W, et al. Pharmacokinetics and pharmacokinetic variability of heroin and its metabolies: review of the literature. Curr Clin Pharmacol 2006; 1(1): 109–18

    Article  PubMed  CAS  Google Scholar 

  35. Mo BP, Way EL. An assessment of inhalation as a mode of administration of heroin by addicts. J Pharmacol Exp Ther 1966; 154: 142–51

    PubMed  CAS  Google Scholar 

  36. Hendriks VM, van den Brink W, Blanken P, et al. Heroin selfadministration by means of ‘chasing the dragon’: pharmacodynamics and bioavailability of inhaled heroin. Eur Neuropsy-chopharmacol 2001; 11: 241–52

    Article  CAS  Google Scholar 

  37. Inturrisi CE, Max MB, Foley KM, et al. The pharmacokinetics of heroin in patients with chronic pain. N Engl J Med 1984; 310: 1213–7

    Article  PubMed  CAS  Google Scholar 

  38. Lotsch J, Skarke C, Schmidt H, et al. Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther 2002; 72: 151–62

    Article  PubMed  CAS  Google Scholar 

  39. Wahlstrom A, Pacifici GM, Lindstrom B, et al. Human liver morphine UDP-glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam. Br J Pharmacol 1988; 94: 864–70

    Article  PubMed  CAS  Google Scholar 

  40. Pacifici GM, Gustafsson LL, Sawe J, et al. Metabolic interaction between morphine and various benzodiazepines. Acta Pharmacol Toxicol (Copenh) 1986; 58: 249–52

    Article  CAS  Google Scholar 

  41. Polettini A, Groppi A, Montagna M. The role of alcohol abuse in the etiology of heroin-related deaths: evidence for pharmacokinetic interactions between heroin and alcohol. J Anal Toxicol 1999; 23: 570–6

    PubMed  CAS  Google Scholar 

  42. Farre M, de la Torre R, Gonzalez ML, et al. Cocaine and alcohol interactions in humans: neuroendocrine effects and cocaethylene metabolism. J Pharmacol Exp Ther 1997; 283: 164–76

    PubMed  CAS  Google Scholar 

  43. Lockridge O, Mottershaw-Jackson N, Eckerson HW, et al. Hydrolysis of diacetylmorphine (heroin) by human serum cholinesterase. J Pharmacol Exp Ther 1980; 215: 1–8

    PubMed  CAS  Google Scholar 

  44. Pindel EV, Kedishvili NY, Abraham TL, et al. Purification and cloning of a broad substrate specificity human liver carboxylesterase that catalyzes the hydrolysis of cocaine and heroin. J Biol Chem 1997; 272: 14769–75

    Article  PubMed  CAS  Google Scholar 

  45. Kamendulis LM, Brzezinski MR, Pindel EV, et al. Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther 1996; 279: 713–7

    PubMed  CAS  Google Scholar 

  46. Ferrari A, Coccia CP, Bertolini A, et al. Methadone: metabolism, pharmacokinetics and interactions. Pharmacol Res 2004; 50: 551–9

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Ministry of Health, Welfare and Sports, The Hague, The Netherlands, who in no way influenced the design of the study nor the contents of this manuscript. This paper is an accurate representation of the study results. The authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands

    Elisabeth J. Rook, Alwin D. R. Huitema & Jos H. Beijnen

  2. Central Committee on the Treatment of Heroin Addicts, Utrecht, The Netherlands

    Wim van den Brink & Jan M. van Ree

  3. Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    Wim van den Brink

  4. Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands

    Jan M. van Ree

  5. Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

Authors
  1. Elisabeth J. Rook
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  2. Alwin D. R. Huitema
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  3. Wim van den Brink
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  4. Jan M. van Ree
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Correspondence to Elisabeth J. Rook.

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Rook, E.J., Huitema, A.D.R., van den Brink, W. et al. Population Pharmacokinetics of Heroin and its Major Metabolites. Clin Pharmacokinet 45, 401–417 (2006). https://doi.org/10.2165/00003088-200645040-00005

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