Effect of enzyme induction on bioavailability of hetacillin in patients treated with anticonvulsants and chlorpromazine

  • P. Galanopoulou
  • Ch. Karageorgiou
  • K. Dimakopoulou
Original Papers


The effect of liver enzyme induction on bioavailability of hetacillin was studied in patients chronically treated with anticonvulsants or chlorpromazine. 24 chronic psychiatric patients classified according to their medication in two groups (anticonvulsants, chlorpromazine) and one group of 11 healthy volunteers, received an i.m. administration of 500 mg hetacillin. Serum levels of arnpicillin derived from hetacillin in blood samples taken 2, 4 and 6 hours after the injection were measured and the half-life of the antibiotic was determined for each group. Urinary D-glucaric acid was considered the induction index. Correlation coefficients between the induction index and pharmacokinetic parameters of hetacillin were also determined. Anticonvulsants and chlorpromazine induced the liver microsomal enzymes as demonstrated by the increased D-glucaric acid excretion (P<0.001 —P<0.05). No statistically significant differences were found in serum levels and half-life of the antibiotic. Correlation coefficients suggest that enzyme induction and hetacillin bioavailability are not significantly related.


Enzyme induction D-glucaric acid psychiatric patients anticonvulsants chlorpromazine hetacillin arnpicillin pharmacokinetics bioavailability 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Perucca E., Hedges A., Makki K.A, Ruprah M, Wilson J.F., Richens A. (1984): A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br. J. Clin. Pharmacol, 18, 401.PubMedGoogle Scholar
  2. 2.
    Stevenson I.H., O’MaUey K., Tumbull M.J., Ballinger B.S. (1972): The effect of chlorpromazine on drug metabolism. J. Pharm. Pharmacol., 24, 577.PubMedCrossRefGoogle Scholar
  3. 3.
    Busfield D., Child K.J., Atkinson R.M., Tomich E.G. (1963): An effect of phenobarhhone on blood levels of griseofulvin in man. Lancet, 2, 1042.PubMedCrossRefGoogle Scholar
  4. 4.
    Busfield D., Child K.J., Tomkh E.G. (1964): An effect of phenobarbitone on griseofulvin metabolism in the rat Br. J. Pharmacol. Chemother., 22, 137.PubMedGoogle Scholar
  5. 5.
    Neuvonen P.J., Pentillä D. (1974): Interaction between doxycycline and barbiturates. Br. Med. J., 1, 535.PubMedCrossRefGoogle Scholar
  6. 6.
    Pentillä D., Neuvonen P.J., Abo K., Lehtovaara R. (1974): Interaction between doxycycline and some antiepileptic drugs. Br. Med. J., 2, 470.CrossRefGoogle Scholar
  7. 7.
    Galanopoulou P., Karageorgiou Ch., Couvaris M., Varonos D. (1980): Influence of liver enzyme induction caused by phénobarbital on the biotransformation of hetacillin in male rats. J. Antimicrob. Chemother, 6, 151.Google Scholar
  8. 8.
    Couvaris M., Galanopoulou P., Karageorgiou Ch., Jalil A., Varonos D. (1985): Bioavailability of hetacillin in rats after liver enzyme induction by various inducers with or without protein binding properties. Eur. J. Drug Metab. Pharmacokinet., 10, 27.PubMedCrossRefGoogle Scholar
  9. 9.
    Couvaris M., Galanopoulou P., Karageorgiou Ch., Theodosopoulos S., Varonos D. (1986): Comparative study of the effects of some inducers with or without protein binding properties on bioavailability of isoxazolyl-penicillins in rats. Eur. J. Drug. Metab. Pharmacokinet., 11, 187.PubMedCrossRefGoogle Scholar
  10. 10.
    Goodman L.S., Oilman A. (1980): The Pharmacological Basis of Therapeutics, 6th edn. New York, Macmülan.Google Scholar
  11. 11.
    Marsh C.A. (1963): Metabolism ofD-glucuronolactone in mammalian systems. Identification ofD-glucaric acid as a normal constituent of urine. Biochem J, 86, 77.PubMedGoogle Scholar
  12. 12.
    Bennett J., Brodie J., Benner E., Kirby W. (1966): Simplified accurate method for antibiotic assay of clinical specimens. Appl. Microbiol., 14, 170.PubMedGoogle Scholar
  13. 13.
    Nousiainen U., Hänninen O. (1981): On the inducibflity of cytosolic and microsomal carboxylesterase by phénobarbital in rat tissues. Acta Pharmacol. Toxicol, 49, 77.CrossRefGoogle Scholar
  14. 14.
    Tuano S.B., Johnson L.D., Brodie J.L., Kirby W.M.M. (1966): Comparative blood levels of hetacillin, ampicillin and penicillin. N. Engl J. Med, 275, 635.PubMedCrossRefGoogle Scholar
  15. 15.
    Kirby W.M.M., Kind A.C., (1967): Clinical pharmacology of ampicfliin and hetacillin. Ann. NY Acad. Sci, 145, 291.PubMedCrossRefGoogle Scholar
  16. 16.
    Pelkonen O., Sotaniemi E.A., Ahokas J.T. (1985): Coumarin 7-hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons. Br. J. Clin. Pharmacol., 19, 59.PubMedGoogle Scholar
  17. 17.
    Ohnhaus E.E., Gerber-Taras E., Park B.K. (1983): Enzyme inducing drug combinations and their effects on liver microsomal enzyme activity in man. Eur. J. Clin. Pharmacol, 24, 247.PubMedCrossRefGoogle Scholar
  18. 18.
    Dimakopoulou K. (1984): Investigation of enzyme induction and levels of antibiotics in psychiatric patients. Doctoral thesis, University of Aniens, Greece.Google Scholar
  19. 19.
    Franklin M.R. (1977): Inhibition of mixed-function oxidations by substrates forming reduced cytochrome P450 metabolic-intermediate complexes. Pharmacol. Ther. A, 2, 227.Google Scholar
  20. 20.
    Bahr C., von Schenkman J.B., Orrenius S. (1972): Effect of phenobarbital and 3,4-benzpyrene treatment of rats on the microsomal binding and hydroxylation of nortriptyline and desmethylimipramine: Evidence of qualitative changes in cytochrome P450 ligand interaction following phénobarbital pretreatment Xenobiotica, 2, 89.CrossRefGoogle Scholar
  21. 21.
    Breyer U. (1972): Perazine, chlorpromazine and imipramine as inducers of microsomal drug metabolism. Naunyn Schmiedebergs Arch. Pharmacol., 72, 277.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • P. Galanopoulou
    • 1
  • Ch. Karageorgiou
    • 1
  • K. Dimakopoulou
    • 2
  1. 1.Department of Experimental Pharmacology, Medical SchoolAthens UniversityAthensGreece
  2. 2.State Mental Hospital of AthensGreece

Personalised recommendations