Douleur et Analgésie

, 11:77 | Cite as

Le métabolisme comme source de variabilité de l'efficacité et de la toxicité des analgésiques

  • P. Bonnabry
  • J. Desmeules
  • P. Dayer
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Résumé

La plupart des analgésiques sont éliminés de l'organisme par biotransformation au niveau hépatique, le plus souvent consécutivement à une oxydation par les cytochromes P450. Compte tenu de la diversité de ce groupe d'enzymes et de l'importante variabilité inter- et intraindividuelle de leur activité, il est indispensable de connaître avec précision les interactions existant entre les médicaments et les différentes isoenzymes.

Les caractéristiques d'élimination des principaux groupes de médicaments utilisés pour combattre les syndromes douloureux (AINS, paracétamol, opioïdes, antidépresseurs) sont passés en revue, tout comme les différents facteurs de variabilité (intrinsèque, génétique et environnementale). Il s'avère qu'il est nécessaire d'être particulièrement vigilant aux substances pouvant moduler la pharmacocinétique des analgésiques majeurs et, en cas d'utilisation des antidépresseurs, de faire preuve d'une certaine prudence, compte tenu de l'important potentiel inhibiteur de certains dérivés. Les facteurs génétiques sont également évoqués, notamment l'incidence de certaines déficiences sur le métabolisme des médicaments.

Grâce à une meilleure connaissance des facteurs de variabilité, il devrait être possible pour les cliniciens d'anticiper un certain nombre de problèmes pouvant aboutir à une toxicité ou au contraire à un échec thérapeutique et ainsi d'améliorer la prise en charge de leurs patients douloureux.

Summary

Most analgesics are eliminated by cytochrome P450-dependent hepatic biotransformation. Owing to the diversity of this enzyme family and to large inter- and intraindividual variabilities in their activity, it is very important to precisely know interactions existing between drugs and specific isozymes.

Elimination characteristics of drugs used to treat painful syndromes (NSAIDs, paracetamol, opioids, antidepressants) are reviewed, as well as variability factors (intrinsic, genetic and environmental). It is necessary to be particularly vigilant to drugs modulating the activity of major analgesics and, for anti-depressants, to care about the inhibition potential of some substances. Genetic deficiencies are mentioned, with a special focus on their incidence on drug metabolism.

Thanks to a better knowledge of variability factors, it should be possible for clinicians to anticipate the occurrence of problems leading to toxicity or to therapeutic failure, and then to improve the treatment of their algic patients.

Key words

Analgesics biotransformation drug interactions cytochrome P-450 polymorphism 
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Bibliographie

  1. 1.
    Omura T. andSato R.: The carbon monoxide binding pigment of liver microsomes. I. Evidence for its hemoprotein nature.J. Biol. Chem. 239, 2370–2378, 1964.PubMedGoogle Scholar
  2. 2.
    Nelson D.R., Koymons L., Kamataki T. et al.: P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature.Pharmacogenetics 6, 1–42, 1996.PubMedCrossRefGoogle Scholar
  3. 3.
    Wrighton S.A. andStevens J.C.: The human hepatic cytochromes P450 involved in drug metabolism.Crit. Rev. Toxicol. 22, 1–21, 1992.PubMedCrossRefGoogle Scholar
  4. 4.
    Bonnabry P., Sievering J., Leemann T. etDayer P.: Approche systématique des interactions médicamenteuses au niveau métabolique: les nouveaux antidépresseurs.Méd. et Hyg. 55, 834–842, 1997.Google Scholar
  5. 5.
    Bertz R.J. andGrannenman G.R.: Use ofin vitro andin vivo data to estimate the likelihood of metabolic pharmacokinetic interactions.Clin. Pharmacokinet. 32, 210–258, 1997.PubMedCrossRefGoogle Scholar
  6. 6.
    Verbeeck R.K.: Pathophysiologic factors affecting the pharmacokinetics of nonsteroidal anti-inflammatory drugs.J. Rheumatol. 15, (suppl. 17), 44–57, 1988.Google Scholar
  7. 7.
    Leemann T., Transon C., Bonnabry P. andDayer P.: A major role for cytochrome P450TB (CYP2C subfamily) in the actions of nonsteroidal antiinflammatory drugs.Drugs Exptl. Clin. Res. 19, 189–195, 1993.Google Scholar
  8. 8.
    Tracy T.S., Rosenbluth B.W., Wrighton S.A., Gonzalez F.J. andKorzekwa K.R.: Role of cytochrome P450 2C9 and an allelic variant in the 4′-hydroxylation of (R)- and (S)-flurbiprofen.Biochem. Pharmacol. 49, 1269–1275, 1995.PubMedCrossRefGoogle Scholar
  9. 9.
    Bonnabry P., Leemann T. andDayer P.: Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam.Eur. J. Clin. Pharmacol. 49, 305–308, 1996.PubMedCrossRefGoogle Scholar
  10. 10.
    Miners J.O., Coulter S., Tukey R.H., Veronese M.E. andBirkett D.J.: Cytochromes P450 1A2 and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen.Biochem. Pharmacol. 51, 1003–1008, 1996.PubMedCrossRefGoogle Scholar
  11. 11.
    Hermans J.J. andThijssen H.H.: Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differencies in their pharmacokinetics.Br. J. Pharmacol. 110, 482–490, 1993.PubMedGoogle Scholar
  12. 12.
    Veronese M.E., Mackenzie P.I., Doecke C.J., Mc Manus M.E., Miners J.O. andBirkett D.J.: Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9.Biochem. Biophys. Res. Commun. 175, 1112–1118, 1991.PubMedCrossRefGoogle Scholar
  13. 13.
    Jollow D.J., Thorgeirsson S.S., Potter W.Z., Hashimoto M. andMitchell J.R.: Acetaminophen-induced hepatic necrosis.Pharmacology 12, 251–271, 1974.PubMedCrossRefGoogle Scholar
  14. 14.
    Patten C.J., Thomas P.E., Guy R.L. et al.: Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics.Chem. Res. Toxicol. 6, 511–518, 1993.PubMedCrossRefGoogle Scholar
  15. 15.
    Dahlin D.C., Miwa G.T., Lu A.Y. andNelson S.D.: N-acetyl-p-benzo-quinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen.Proc. Natl. Acad. Sci. USA 81, 1327–1331, 1984.PubMedCrossRefGoogle Scholar
  16. 16.
    Osborne R., Joel S., Trew D. andSlevin M.: Morphine and metabolite behaviour after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide.Clin. Pharmacol. Ther. 47, 12–19, 1990.PubMedGoogle Scholar
  17. 17.
    Hagen N., Thirlwell M.P., Dhaliwal H.S., Babul N., Harsanyi Z. andDarke A.C.: Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone.J. Clin. Pharmacol. 35, 37–44, 1995.PubMedGoogle Scholar
  18. 18.
    Milne R.W., Nation R.L. andSomogyi A.A.: The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine.Drug. Metab. Rev. 28, 345–472, 1996.PubMedCrossRefGoogle Scholar
  19. 19.
    Desmeules J., Gascon M.P., Dayer P. andMagistris M.: Impact of environmental and genetic factors on codein analgesia.Eur. J. Clin. Pharmacol. 41, 23–26, 1991.PubMedCrossRefGoogle Scholar
  20. 20.
    Fromm M.F., Hofmann U., Griese E.U. andMikus G.: Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans.Clin. Pharmacol. Ther. 58, 374–382, 1995.PubMedCrossRefGoogle Scholar
  21. 21.
    Otton S.V., Schadel M., Cheung S.W., Kaplan H.L., Busto U.E. andSellers E.M.: CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone.Clin. Pharmacol. Ther. 54, 463–472, 1995.Google Scholar
  22. 22.
    Iribarne C., Berthou F., Baird S., Dréano Y. et al.: Involvment of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes.Chem. Res. Toxicol. 9, 365–373, 1996.PubMedCrossRefGoogle Scholar
  23. 23.
    Iribarne C., Picart D., Dreano Y., Bail J.P. andBerthou F.: Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes.Life Sci. 60, 1953–1964, 1997.PubMedCrossRefGoogle Scholar
  24. 24.
    Tateishi T., Krivoruk Y., Ueng Y.F., Wood A.J., Guengerich F.P. andWood M.: Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation.Anesth. Analg. 82, 167–172, 1996.PubMedCrossRefGoogle Scholar
  25. 25.
    Labroo R.B., Thummel K.E., Kunze K.L., Podoll T., Trager W.F. andKharasch E.D.: Catalytic role of cytochrome P4503A4 in multiple pathways of alfentanil metabolism.Drug. Metab. Dispos. 23, 490–496, 1995.PubMedGoogle Scholar
  26. 26.
    Paar W.D., Frankus P. andDengler H.J.: The metabolism of tramadol by human liver microsomes.Clin. Invest. 70, 708–710, 1992.CrossRefGoogle Scholar
  27. 27.
    Liu Z., Mortimer O., Smith C.A. andRane A.: Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism.Br. J. Clin. Pharmacol. 39, 77–80, 1995.PubMedGoogle Scholar
  28. 28.
    Gorski J.C., Jones D.R., Wrighton S.A. andHall S.D.: Characterization of dextromethorphan N-demethylation by human liver microsomes.Biochem. Pharmacol. 48, 173–182, 1994.PubMedCrossRefGoogle Scholar
  29. 29.
    Hamelin B.A., Turgeon J., Vallee F., Belanger P.M., Paquet F. andLe Bel M.: The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquine.Clin. Pharmacol. Ther. 60, 512–521, 1996.PubMedCrossRefGoogle Scholar
  30. 30.
    Transon C., Lecoeur S., Leemann T., Beaune P. andDayer P.: Interindividual variability in catalytic activity and immunoreactivity of three human liver cytochrome P450 isozymes.Eur. J. Clin. Pharmacol. 51, 79–85, 1996.PubMedCrossRefGoogle Scholar
  31. 31.
    Dayer P., Leemann T., Marmy A. andRosenthaler J.: Interindividual variation of beta-adrenoceptor blocking drugs, plasma concentration and effect: influence of genetic status on behaviour of atenolol, bopindolol and metoprolol.Eur. J. Clin. Pharmacol. 28, 149–153, 1985.PubMedCrossRefGoogle Scholar
  32. 32.
    Bertilsson L., Mellstrom B., Sjokvist F., Martenson B. andAsberg M.: Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications.Lancet 1, 650–651, 1980.Google Scholar
  33. 33.
    Balant-Gorgia A.E., Balant L.P., Genet C., Dayer P., Aeschlimann J.M. andGarrone G.: Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites.Eur. J. Clin. Pharmacol. 31, 449–455, 1986.PubMedCrossRefGoogle Scholar
  34. 34.
    Mahgoub A., Idle J.R., Dring L.G., Lancester R. andSmith R.L.: Polymorphic hydroxylation of debrisoquine in man.Lancet 2, 584–586, 1977.PubMedCrossRefGoogle Scholar
  35. 35.
    Eichelbaum M., Spannbrucker N., Steincke B. andDengler J.J.: N-oxydation of sparteine in man: a new pharmacogenetic defect.Eur. J. Clin. Pharmacol. 16, 183–187, 1979.PubMedCrossRefGoogle Scholar
  36. 36.
    Wilkinson G.R., Guengerich F.P. andBranch R.A.: Genetic polymorphism of S-mephenytoin hydroxylation.Pharmacol. Ther. 43, 53–76, 1989.PubMedCrossRefGoogle Scholar
  37. 37.
    Rolan P.E.: Plasma protein binding displacement interactions — why are they still regarded as clinically important?Br. J. Clin. Pharmacol. 37, 125–128, 1994.PubMedGoogle Scholar
  38. 38.
    Mac Kichan J.J.: Protein binding drug displacement interactions. Fact or fiction?Clin. Pharmacokinet. 16, 65–73, 1989.CrossRefGoogle Scholar
  39. 39.
    Bonnabry P., Leemann T. andDayer P.: Interactions between oral anticoagulants and NSAIDs: a key role for cytochrome P450TB (CYP2C9).Thérapie 50 (suppl. 1), 55, 1995.Google Scholar
  40. 40.
    Bonnabry P., Desmeules J., Rudaz S., Leemann T., Veuthey J.L. andDayer P.: Stereoselective interaction between piroxicam and acenocoumarol.Br. J. Clin. Pharmacol. 41, 525–530, 1996.PubMedCrossRefGoogle Scholar
  41. 41.
    Wu D., Otton S.V., Sproule B.A., et al.: Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone.Br. J. Clin. Pharmacol. 35, 30–34, 1993.PubMedGoogle Scholar
  42. 42.
    Ducharme M.P., Provenzano R., Dehoorne-Smith M. andEdwards D.J.: Through concentrations of cyclosporine in blood following administration with grapefruit juice.Br. J. Clin. Pharmacol. 36, 457–459, 1993.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1998

Authors and Affiliations

  • P. Bonnabry
    • 2
    • 1
  • J. Desmeules
    • 2
    • 1
  • P. Dayer
    • 2
    • 1
  1. 1.Centre multidisciplinaire d'évaluation et de traitement de la douleurHôpitaux Universitaires GenèveGenève
  2. 2.Hôpitaux Universitaires GenèveGenève 14

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