Clinical Pharmacokinetics

, Volume 20, Issue 2, pp 123–134 | Cite as

Clinical Pharmacokinetics of N-Acetylcysteine

  • Mack R. Holdiness
Drug Disposition

Summary

N-Acetylcysteine is useful as a mucolytic agent for treatment of chronic bronchitis and other pulmonary diseases complicated by the production of viscous mucus. It is also used as an antidote to paracetamol (acetaminophen) poisoning and found to be effective for the prevention of car-diotoxicity by doxorubicin and hae norrhagic cystitis from oxazaphosphorines.

After an oral dose of N-acetylcysteine 200 to 400mg the peak plasma concentration of 0.35 to 4 mg/L is achieved within 1 to 2 hours. Although the data are conflicting, it appears that the administration of charcoal may interfere with drug absorption, with up to 96% of the drug adsorbed on to the charcoal. Information on absorption in the presence of food or other drugs is not available. The volume of distribution ranges from 0.33 to 0.47 L/kg and protein binding is significant, reaching approximately 50% 4 hours after the dose. Pharmacokinetic information is not available as to whether or not N-acetylcysteine crosses the blood-brain barrier or placenta, or into breast milk. Renal clearance has been reponed as 0.190 to 0.211 L/h/ke and approximately 70% of the total body clearance is nonrenal. Following oral administration, reduced /V-acetyl-cysteine has a terminal half-life of 6.25h. Little is known of the metabolism of this agent, although it is believed to be rapidly metabolised and incorporated on to proteins. The major excretory product is inorganic sulphate.

Frequently reported side effects are nausea, vomiting and diarrhoea. Biochemical and hae-matological adverse effects are observed but are not clinically relevant. Drug interactions of clinical significance have been observed with paracetamol, glutathione and anticancer agents.

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References

  1. Anzai N, Kiura T, Chida S, Tanaka T, Takahashi H, et al. A sensitive fluorometric determination of N-acetylcysteine in biological fluids by HPLC. Journal of Pharmaceutical Sciences of Japan 101: 1002–1009, 1981Google Scholar
  2. Bowman G, Backer U, Larsson S, Melander B, Whalander L. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. European Journal of Respiratory Diseases 64: 405–415, 1983Google Scholar
  3. Bonanomi L, Gazzaniga A. Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. European Journal of Respiratory Diseases 61 (Suppl. 11): 45–51, 1980Google Scholar
  4. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-acetylcysteine in man. European Journal of Clinical Pharmacology 31: 217–222, 1986PubMedCrossRefGoogle Scholar
  5. Bronstein AC, Rumack BH. Acute acetaminophen overdose during pregnancy: review of fifty-five cases. Abstract. American Association of Poison Control Centers, October 7-12, 1984Google Scholar
  6. Cotgreave IA, Eklund A, Larsson K, Moldeus P. No penetration of orally administered N-acetyltysteine into bronchoalveolar lavage fluid. European Journal of Respiratory Diseases 70: 73–77, 1987PubMedGoogle Scholar
  7. Cotgreave IA, Moldeus P. Methodologies for the analysis of reduced and oxidized’ N-acetylcysteine in biological systems. Biopharmaceutical Drug Disposition 8: 365–375, 1987CrossRefGoogle Scholar
  8. DeCaro L, Ghizzi A, Costa R, Longo A, Ventresca GP, et al. Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers. Arzneimittel-Forschung 39: 382–386, 1989Google Scholar
  9. Drummer OH, Christophidis N, Horowitz JD, Louis WJ. Measurement of penicillamine and N-acetylcysteine in human blood by HPLC and electrochemical detection. Journal of Chromatography — Biomedical Applications 374: 251–257, 1986PubMedCrossRefGoogle Scholar
  10. Frank H, Thiel D. Determination of N-acetylcysteine in biological fluids. Journal of Chromatography — Biomedical Applications 309: 261–267, 1984PubMedCrossRefGoogle Scholar
  11. Hannestad U, Sorbo B. Determination of 3-mercaptolactate, mer-captoacetate and N-acetylcysteine in urine by gas chromatography. Clinica Chimica Acta 95: 189–200, 1979CrossRefGoogle Scholar
  12. Holdiness MR, Morgan LR, Gillen LE. HPLC determination of N-acetylcysteine in human serum following acetaminophen overdosage. Journal of Chromatography — Biomedical Applications 382: 99–106, 1986PubMedCrossRefGoogle Scholar
  13. Johansson M, Westerlund D. Determination of N-acetylcysteine, intact and oxidized, in plasma by column liquid chromatography and post column derivatization. Journal of Chromatography 385: 343–356, 1987PubMedCrossRefGoogle Scholar
  14. Kagedal B, Kallberg M, Martensson J. Determination of non-protein bound N-acetylcysteine in plasma by HPLC. Journal of Chromatography — Biomedical Applications 311: 170–175, 1984PubMedCrossRefGoogle Scholar
  15. Klein-Schwartz W, Oderda GM. Adsorption of oral antidotes for acetaminophen poisoning (methionine and N-acetylcysteine) by activated charcoal. Clinical Toxicology 18: 283–290, 1981PubMedCrossRefGoogle Scholar
  16. Kok WT, Halvax JJ, Frei RW. Comparison of electrochemical detection methods in liquid chromatography for determination of N-acetylcysteine in plasma. Journal of Chromatography 352: 27–33, 1986PubMedCrossRefGoogle Scholar
  17. Lauterburg BH, Corcoran GB, Mitchell JR. N-acetylcysteine pro-teas against the hepatotoxicity of acetaminophen by reducing the reactive metabolites in rats in vivo. Gastroenterology 82: 1234, 1982Google Scholar
  18. Lewis PA, Woodward AJ, Maddock J. HPLC assay for N-acetylcysteine in plasma and urine. Journal of Pharmacuetical Sciences 73: 996–998, 1984CrossRefGoogle Scholar
  19. Lewis PA, Woodward AJ, Maddock J. Improved method for the determination of N-acetylcysteine in human plasma by HPLC. Journal of Chromatography 327: 261–267, 1985PubMedCrossRefGoogle Scholar
  20. Maddock J. Biological properties of a cetylcysleine: assay development and pharmacokinetic studies. European Journal of Respiratory Diseases 61 (Suppl. Ill): 52–58, 1980Google Scholar
  21. Miller LF & Rumack BH. Clinical safety of high oral doses of acetylcysteine. Seminars in Oncology 10: 76–85, 1983PubMedGoogle Scholar
  22. Moldeus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration 50 (Suppl. 1): 31–42, 1986PubMedCrossRefGoogle Scholar
  23. Morgan LR, Donley PJ, Harrison EF, Hunter HL. Protective effect of N-acetylcysteine on the urotoxicity produced by oxa-zaphosphosine without interference with anticancer activity. European Journal of Cancer and Clinical Oncology 18: 113–114, 1982CrossRefGoogle Scholar
  24. Morgan LR, Holdiness MR, Gillen LE. N-acetylcysteine: its bioavailability and interaction with ifosfamide metabolites. Seminars in Oncology 10: 56–61, 1983PubMedGoogle Scholar
  25. Multicenter Study Group. Long term oral acetylcysteine in chronic bronchitis, a double blind controlled study. European Journal of Respiratory Diseases 61 (Suppl. Ill): 93–108, 1980Google Scholar
  26. Norpoth K. Studies on the metabolism of isophosphamide in man. Cancer Treatment Reports 60: 437–443, 1976PubMedGoogle Scholar
  27. North DS, Peterson RG, Krenzelok EP. Effects of activated charcoal administration on acetylcysteine serum levels in humans. American Journal of Hospital Pharmacy 38: 1022–1024, 1981PubMedGoogle Scholar
  28. Olsson B, Johansson M, Gabrielsson J, Holme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. European Journal of Clinical Pharmacology 34: 77–82, 1988PubMedCrossRefGoogle Scholar
  29. Pirie NW, Hele TS. Studies in the sulphur metabolism of the dog. The preparation and metabolism of d-acetylcysteine. Biochemical Journal 27: 1716–1718, 1933PubMedGoogle Scholar
  30. Prescott LF, Critchley JAJH. The treatment of acetaminophen poisoning. Annual Review of Pharmacology and Toxicology 23: 87–101, 1983PubMedCrossRefGoogle Scholar
  31. Raggi MA, Cavrini V, DiPietra AM. Colorimetric determination of acetylcysteine, penicillamine, and mercaptopropionolgly-cine in pharmaceutical dosage forms. Journal of Pharmaceutical Sciences 71: 1384–1986, 1982PubMedCrossRefGoogle Scholar
  32. Rodenstein D, DeCoster A, Gazzaniga A. Pharmacokinetics of oral acetylcysteine: absorption, binding and metabolism in patients with respiratory disorders. Clinical Pharmacokinetics 3: 247–254, 1978PubMedCrossRefGoogle Scholar
  33. Rodenstein D, DeCoster A, Gazzangia A. Pharmacokinetics of oral acetylcysteine: absorption, binding and metabolism in patients with respiratory disorders. European Journal of Respiratory Diseases 61 (Suppl. Ill): 383–387, 1980Google Scholar
  34. Sheffner AL, Medler EM, Bailey KR, Gallo DG, Mueller A, et al. Metabolic studies wth acetylcysteine. Biochemical Pharmacology 15: 1523–1535, 1966PubMedCrossRefGoogle Scholar
  35. Toyooka T, Imai K. HPLC and fluorometric detection of biologically important thiols, derivatized with ammonium 7-lluo-robenzo-2-oxa-1, 3-diazole-4-sulphonate. Journal of Chromatography 282: 495–500, 1983CrossRefGoogle Scholar
  36. Unverferth DV, Mehegan JP, Nelson RW, Scott CC, Leier CV, et al. The efficacy of N-acetylcysteine in preventing doxorubicin induced cardiomyopathy in dogs. Seminars in Oncology I ft 2-6, 1983aGoogle Scholar
  37. Unverferth DV, Fertel RH, Balcerzak SP, Magorien RD, O’Dor-isio MS. N-acetylcysteine prevents the doxorubicin induced decrease of cyclic GMP. Seminars in Oncology 10: 49–52, 1983bPubMedGoogle Scholar
  38. Ziment I. Acetylcysteine: a drug with an interesting past and a fascinating future. Respiration 50: 26–30, 1986PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Mack R. Holdiness
    • 1
  1. 1.Lakeside HospitalMetairie (New Orleans)USA

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