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Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers

Summary

Plasma levels and urinary excretion of lormetazepam (Noctamid ®-ampoules; 2 mg/10 ml) were studied after i.v. (0.015 mg/kg b.w.) and after p.o (0.03 mg/kg b.w.) administration of the drug to five patients with cirrhosis of the liver (C) and to five young male volunteers (N).

The cirrhotic patients exhibited higher drug plasma levels (Cmax p.o.: 11–43 ng/ml [C] vs. 11–16 ng/ml [N]) and higher AUC0–24 values of the unchanged drug (i.v.: 66–102 ng.h/ml [C] vs. 54–72 ng.h/ml [N]; p.o.: 83–188 ng.h/ml [C] vs. 74–113 ngJi/ml [N]). The absolute bioavailability was increased in (he C-group with 57–134% vs. 52–84% [N]. The total plasma clearance of lormetazepam was 3 ml/min/kg in the C-group and 4 ml/min/kg in the N-group and thus within the range known for elderly and young male subjects. Conversely to the parent compound, the AUC-figures of its 3-OH-glucuronide were higher in the N-group (346–434 ng.h/ml) than in the C-group (149–371 ng.h/ml). In 24 h pooled urine samples of both groups, the glucuronide of lorazepam, the N-demethylated metabolite, accounted for approximately 5–14% of the dose fraction excreted as lormetazepam glucuronide.

Apart from increased levels of the unchanged drug due to porto-systemic shunt and/or disease-dependent lower glucuronidation rate, the pharmacokinetics of lormetazepam were not altered in cirrhotic patients. It can therefore be concluded that for this group of patients the drug can be administered according to the same dose regimen as that used for normal subjects.

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References

  1. 1.

    Oswald I., Adam K., Burrow S., Idzikowski C. (1979): The effect of two hypnotics on sleep, subjective feelings and skilled performance. In: Passonant R., Oswald I. (eds), Pharmacology of the state of alertness. Oxford, Pergamon Press, pp. 51–63.

  2. 2.

    Hümpel M., Nieuweboer B., Milius W., Hanke H., Wendt H. (1980): Kinetics and biotransformation of lormetazepam. II. Radioimmunologic determination in plasma and urine of young and elderly subjects: First-pass effect Clin. Pharmacol. Ther, 28, 673–679.

  3. 3.

    Hümpel M., Illi V., Milius W., WendtH., Kurowski M. (1979): The pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans. I. Absorption, distribution, elimination and metabolism of lormetazepam-5-14C. Eur. J. Drug Metab. Pharmacokinet., 4, 237–243.

  4. 4.

    Mayo B.C., Hawkins D.R., Hümpel M., Chasseaud L.F., Girkin R. (1980): The biotransformation of14C-lormetazepam in dogs, rabbits, rats and the rhesus monkey. Xenobiotica, 10, 401–413.

  5. 5.

    Girkin R., Baldock G.A., Chasseaud L.F., Hümpel M., Hawkins D.R., Mayo B.C. (1980): The absorption, distribution and excretion of14C-lormetazepam in dogs, rabbits, rats and the rhesus monkey. Xenobiotica, 10, 401–413.

  6. 6.

    Hellstern A., Hildebrand M., Hümpel M., Madetzki Chr. (1990): Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique. Int. J. Clin. Pharm. Ther. Toxicol. (In Press)

  7. 7.

    Bosch J., Groszmann R.J., (1984): Measurement of azygos blood flow by a continuous thermal dilution technique: An index of blood flow through gastroesophageal colaterals in cirrhosis. Hepatology, 4, 424–429.

  8. 8.

    Wilkinson G.R., Branch R.A (1984): In: Benet L.Z. (ed), Pharmacokinetic basis for drug treatment. New York, Raven Press, pp. 49–61.

  9. 9.

    Greenblatt D.J., Shader R.I., Abemethy D.R., Ochs H.R., Divoll M., Sellers E.M. (1983): Benzodiazepines and the challenge of pharmacokinetic taxonomy. In: Usdin E. et al (eds), Pharmacology of benzodiazepines. Basel, Verlag Chemie, pp. 257–269.

  10. 10.

    Shull H.J., Wilkinson G.R., Johnson R., Schenker S. (1976): Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann. Intern. Med., 84, 420–425.

  11. 11.

    Kraus J.W., Desmond P.V., Marshall J.P., Johnson R.F., Schenker S., Wilkinson G.R. (1988): Effects of aging and liver disease on disposition of lorazepam. Clin. Pharmacol. Ther., 24, 411–419.

  12. 12.

    Pirttiaho H.I., Sotaniemi E.A., Ablqvist J., Pitkänen U., Pelkonen R.O., (1978): Liver size and indices of drug metabolism in alcoholics. Eur. J. Clin. Pharmacol., 13, 61–67.

  13. 13.

    Kitteringham N.R., Büstgens L., Brundert E., Mineshita S., Ohnhaus E.E. (1984): The effect of liver cirrhosis on the pharmacokinetics of phenprocoumon. Eur. J. Clin Pharmacol., 26, 65–70.

  14. 14.

    Tschanz C., Wilson R.L., Shand D.G. (1983): The effects of cirrhosis on temazepam elimination. Clin, Pharmacol. Ther., 33A, 218.

  15. 15.

    Sellers E.M., Greenblatt D.J., Giles H.G., Naranjo C.A., Kaplan H., MacLeod S.M. (1979): Chlordiazepoxide and oxazepam disposition in cirrhosis. Clin. Pharmacol. Ther., 26, 240–246.

  16. 16.

    Somogyi A., Rolan P. (1986): Drug disposition and dosing in hepatic disease. Med. J. Aust., 145, 284–289.

  17. 17.

    Child Ch.G. (1954): The hepatic circulation and portal hypertension. Philadelphia, Saunders.

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Correspondence to M. Hildebrand.

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Hildebrand, M., Hellstern, A., Hümpel, M. et al. Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers. Eur. J. Drug Metab. Pharmacokinet. 15, 19–26 (1990). https://doi.org/10.1007/BF03190123

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Keywords

  • Lormetazepam
  • pharmacokinetics
  • bioavailability
  • cirrhotic patients
  • normal volunteers