Liver disease in man is associated with a variety of pathophysiological processes which may influence the disposition of drugs in several ways. Interpretation of the observed pharmacokinetic changes in liver disease requires an understanding of the relationship between systemic drug clearance (Cls), volume of distribution (Vd)and the elimination half-life [t1/2(β)], i.e. t1/2(β) = 0.693· Vd/Cls.Half-life will be a measure of the fluctuation in drug level one may expect with continued administration of a drug while clearance will determine the dose required to achieve a particular steady state level. Liver disease may affect clearance and volume of distribution and so produce changes in half-life; in addition, alterations in plasma binding of drugs may occur and so influence free (unbound) drug levels. It is also possible that the end organ response, particularly in the case of sedative drugs, may be affected by liver disease.
Other factors such as age, nutrition, smoking, and concomitant drug therapy may also influence drug elimination in patients with liver disease. At the present time, caution should be exercised in prescribing drugs to patients with liver disease and the dose should be titrated to the clinical response. The development of liver function’ tests using model or marker drugs may offer some help to the prescriber in the future and enable a less empirical approach.
KeywordsMorphine Liver Disease Diazepam Chronic Liver Disease Isoniazid
Unable to display preview. Download preview PDF.
- Andreasen, P.B.; Ranek, L.; Statland, B.E. and Tygstrup, N.: Clearance of antipyrine. Dependence of quantitative liver function. Eur. J, clin. Invest 4: 129–134 (1974).Google Scholar
- Azzollini, F.; Gazzaniga, A.; Lodola, E. and Natangelo, R.: Elimination of chloramphenicol and thiamphenicol in subjects with cirrhosis of the liver. International Journal of Clinical Pharmacology 6: 1059–1065 (1972).Google Scholar
- Bircher, J.; Kupfer, A.; Gikalov, I. and Preisig, R.: Aminopyrine demethylation measured by breath analysis in cirrhosis. Clinical Pharmacology and Therapeutics 20: 484–492 (1975).Google Scholar
- Breen, K.J.; Desmond, P.V.; Bury, R. Calder, I. and Mashford, M.L.: A l4C-phenacetin breath test in the assessment of hepatic function. Gastroenterology 72: 1033 (1977).Google Scholar
- Breimer, D.D.: in Pharmacokinetics of Hypnotic Drugs, pp.291–307 (Drukkerij-Vitgeverij Brakkenstein, Nijmegen 1974).Google Scholar
- Briant, R.H.: Dorrington, R.E.; Creal, J. and Williams, F.M.: Rate of acetaminophen metabolism in the elderly and the young. Journal of American Geriatrics Society 24: 359–361 (1976).Google Scholar
- Davis, M. and Rossouw, J.E.: Drug metabolism in liver disease; in Grahame-Smith (Ed.), Drug Interactions, pp. 197–207 (University Park Press, Baltimore 1977).Google Scholar
- Farrell, G.C; Cooksley, W.G.E.; Powell, L.W. and Hart, P.: Interaction between liver disease and chronic drug ingestion on hepatic drug metabolism. Gastroenterology 71: 905 (1976).Google Scholar
- Fessell, J.M. and Conn, H.O.: An analysis of the causes and prevention of hepatic coma. Gastroenterology 62: 191 (1972).Google Scholar
- Finlayson, N.D.C; Prescott, L.F.; Adjepon-Yamoiah, K.K. and Forrest, J.A.H.: Antipyrine, lidocaine and paracetamol metabolism in chronic liver disease. Gastroenterology 67: 790 (1974).Google Scholar
- Hepner, G.W.; Vesell, E.S.; Lipton, A.; Harvey, H.A.; Wilkinson, G.R. and Schenker, S.: Disposition of aminopyrine, antipyrine, diazepam, and indocyanine green in patients with liver disease or on anticonvulsant therapy: Diazepam breath test and correlation in drug elimination. Journal of Laboratory and Clinical Medicine 90: 440–456 (1977).PubMedGoogle Scholar
- Hoffman, T.A.; Cestero, R. and Bullock, W.E.: Pharmacodynamics of carbenicillin in hepatic and renal failure. Annals of Inmjl Medicine 73: 173–178 (1970).Google Scholar
- Kraus, J.W.; Marshall, J.P.; Johnson, R.; Wilkinson, G.R. and Schenker, S.: Lorazepam elimination in liver disease, Gastroenterology 73: 1228 (1977).Google Scholar
- Kunin, CM.; Glazko, A.J. and Finland, M.: Persistence of antibiotics in the blood of patients with acute renal failure. II. Chloramphenicol and its metabolic products in the blood of patients with severe renal disease or hepatic cirrhosis. Journal of Clinical Investigation 38: 1498–1508 (1959).PubMedCrossRefGoogle Scholar
- Roberts, R.K.; Wilkinson, G.R.: Branch, R.A. and Schenker, S.: The effect of age and liver disease on the disposition and elimination of chlordiazepoxide (Librium®). Gastroenterology (In press, 1978).Google Scholar
- Wilkinson, G.R.: Pharmacokinetics in disease states modifying body perfusion; in Benet (Ed), The Effect of Disease States on Drug Pharmacokinetics, pp. 13–32 (American Pharmaceutical Association, Washington 1976).Google Scholar
- Williams, R.L.; Blaschke, T.F.; Meffin, P.J.; Melmon, K.L. and Rowland, M.: The influence of acute viral hepatitis on lidocaine disposition in man. Clinical Research 23: 226A (1975).Google Scholar