Summary
A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250 mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.
Similar content being viewed by others
References
Ballinger, B., Browning, M., O'Malley, K., Stevenson, I. H.: Drugmetabolizing capacity in states of drug dependence and withdrawal. Br. J. Pharmacol.45, 638–643 (1972)
Branch, R.A., Herbert, C.M., Read, A.E.: Determinants of serum antipyrine half-lives in patients with liver disease. Gut14, 569–573 (1973)
Brodie, B.B. and Axelrod, J.: The fate of antipyrine in man. J. Pharmacol. Exp. Ther.,98, 97–104 (1950)
Capelle, P., Dhumeaux, D., Mora, M., Feldman, G., Berthelot, P.: Effects of rifampicin on liver function in man. Gut13, 366–371 (1972)
Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev.19, 317–366 (1967)
Cucinell, S. A., Conney, A. H., Sansur, M., Burns, J. J.: Drug interactions in man. I. Lowering effect of phenobarbital on plasma levels of bishydroxycoumarin (dicumarol) and diphenylhyantoin (dilantin). Clin. Pharmacol. Ther.6, 420–429 (1965)
Farrell, G. C., Cooksley, W. G. E., Hart, P., Powell, L. W.: Drug metabolism in liver disease. Identification of patients with impaired hepatic drug metabolism. Gastroenterology75, 580–588 (1978)
Farrell, G. C., Cooksley, W. G. E., Powell, L. W.: Drug metabolism in liver disease. Activity of hepatic drug metabolizing enzymes. Clin. Pharmacol. Ther. (in press)
Fessel, J. M., Conn, H. O.: An analysis of the causes and prevention of hepatic coma. Gastroenterology,62, 191 (1972)
Hart, P., Farrell, G. C., Cooksley, W. G. E., Powell, L. W.: Enhanced drug metabolism in cigarette smokers. Br. med. J.2, 147–149 (1976)
Held, H. and von Oldershausen, H.-F.: Zur Pharmakokinetic von Meprobamat bei chronischen Hepatopathien und Arzneimittelsucht. Klin. Wochenschr.47, 78–80 (1969)
Leevy, C. M., ten Hove, W., Opper, A., Popovic, S.: Influence of ethanol and microsomal drugs on hepatic hemodynamics. Ann. NY Acad. Sci.170, 315–330 (1970)
Levi, A. J., Sherlock, S., Walker, D.: Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous drug therapy. Lancet1968/I, 1275–1279
Lichter, M., Black, M., Arias, I. M.: The metabolism of antipyrine in patients with chronic renal failure. J. Pharmacol. Exp. Ther.187, 612–619 (1973)
Prescott, L. F., Adjepon-Yamoah, K. K., Roberts, E.: Rapid gasliquid chromatographic estimation of antipyrine in plasma. J. Pharma. Pharmacol.25, 205–207 (1973)
Sharpless, S. K.: Hypnotics and Sedatives. In: The Pharmacological Basis of Therapeutics. Eds. L. S. Goodman and A. Z. Gilman, MacMillan, London. pp. 121–134 (1970)
Smith, S. E. and Rawlins, M. D.: Pharmacokinetics. In: Variability in Human Drug Response, Butterworths, London. pp. 8–24 (1973)
Thaler, M. N., Dallman, P. R., Goodman, J.: Phenobarbital-induced changes in NADPH-cytochrome C reductase and smooth endoplasmic reticulum in human liver. Pediatrics80, 302–310 (1972)
Vesell, E. S. and Page, J. G.: Genetic control of phenobarbital-induced shortening of plasma antipyrine half-lives in man. J. clin. Invest.48, 2202–2209 (1969)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Farrell, G.C., Cooksley, W.G.E. & Powell, L.W. Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease. Eur J Clin Pharmacol 16, 113–117 (1979). https://doi.org/10.1007/BF00563117
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00563117