Protein Binding and Kinetics of Drugs in Liver Diseases
- 60 Downloads
Although the liver is the major site for drug biotransformation, the effect of hepatic dysfunction on drug disposition has not been consistent or predictable. Most early studies of drug kinetics in liver disease measured only half-life. Only in the past few years has it been realised that liver diseases can affect drug absorption, hepatic metabolism, tissue distribution, and protein binding, which complicate interpretation of any change, or lack of change in drug half-life. Furthermore, it is now apparent that the efficiency with which a drug is metabolised by the liver, the extent of binding to blood constituents, and the aetiology and stage of the hepatic disorder are each important in determining whether significant alterations in drug disposition will occur.
A pharmacokinetic perfusion model which takes into account many of the above factors has been proposed, and appears to be useful for predicting changes in the disposition of rapidly metabolised compounds. Nevertheless, the state of knowledge about those factors which limit the rate of metabolism of individual drugs or classes of drugs is inadequate, and no general model or guidelines which are useful clinically have been developed.
Patients with hepatic disorders may show increases or decreases in sensitivity independent of alterations in drug disposition. The clinician caring for such patients must be cautious about the use of any drugs, and rely heavily on careful patient observation to determine efficacy or toxicity.
KeywordsLiver Disease Clinical Pharmacology Plasma Protein Binding Tolbutamide Antipyrine
Unable to display preview. Download preview PDF.
- Andreason, P.B.; Ranek, L.; Statland B.E. and Tygstrup, N.: Clearance of Antipyrine-dependence of quantitative liver function. European Journal of Clinical Investigation. 4: 129–134 (1974).Google Scholar
- Adreasen, P.B. and Vesell, E.S.: Comparison of plasma levels of antipyrine, tolbutamide, and warfarin after oral and intravenous administration. Clinical Pharmacology and Therapeutics 16: 1059–1065 (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: 130–134 (1972).Google Scholar
- Bennhold, H.: Die vekikelfunction der bluteiweisskorper. Chapter in Die Eiweisskorper des Blutplasmas by H. Bennhold, E. Kylin and S. Rusznyak. Steinkopf, Leipzig (1938).Google Scholar
- Branch, R.A.; Shand, D.G.; Wilkinson, G.R. and Nies, A.S.: Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme and induction and increased hepatic blood flow. Journal of Clinical Investigation 53: 1101–1107 (1974).PubMedCrossRefGoogle Scholar
- Breckenridge, A.: Pathophysiological factors influencing drug kinetics. Acta Pharmacologica Toxicologica (Suppl 3) 29: 225–232 (1971).Google Scholar
- Gibaldi, M. and Perrier, D.: Pharmacokinetics (Marcel Dekker, Inc. New York, 1975).Google Scholar
- Goldstein, A.: The interactions of drugs and plasma proteins. Pharmacological Reviews 1: 102–165 (1949).Google Scholar
- Gordon, R.C.; Regamey, C. and Kirby, W.M.M.: Serum protein binding of erythromycin, lincomycin and clindamycin. Journal of Pharmacology and Science 1074–1077 (1973).Google Scholar
- Mendenhall, C.L.; Robinson, J.D. and Morgan, D.D.: Chlordiazepoxide (Librium) therapy in hepatic insufficiency (Abstract). Gastroenterology 69: 845 (1975).Google Scholar
- Nies, A.S.; Shand, D.G. and Branch, R.A.: Hemodynamic drug interactions: the effects of altering hepatic blood flow on drug disposition; in Morselli, Garattini and Cohen (Eds) Drug Interactions, pp.231–240 (Raven Press, New York 1974).Google Scholar
- O’Reilly, R.A.; Welling. P.G. and Wagner, J.G.: Pharmacokinetics of warfarin following intravenous administration to man. Thrombosis of Diathesis Haemorrhagica 25: 178–186 (1971).Google Scholar
- Pang, H.K.S. and Rowland, M.: Hepatic clearance of drugs: Discrimination between two models, in Abstracts of the 16th National Meeting of the APhA Academy of Pharmaceutical Sciences, San Francisco, Vol. 2, Washington, D.C. (1975).Google Scholar
- Reigelman, S. and Rowland, M.: Effect of route of administration of drug disposition; in Teorell, Dedrick, and Condliffe (Eds) Pharmacology and Pharmacokinetics, p.87–104 (Plenum Press, New York-London, 1974).Google Scholar
- Rowland, M.; Blaschke, T.F.; Meffin, P.J. and Williams, R.L.: Pharmacokinetics in disease states modifying hepatic and metabolic function, in L.Z. Benet, Ed. Effect of Disease States on Drug Pharmacokinetics, p. 53–74. (American Pharmaceutical Association, Academy of Pharmaceutical Sciences, Washington, D.C, 1976).Google Scholar
- Williams, R.L.; Blaschke, T.F.; Meffin, P.J.; Melmon, K.L. and Rowland, M.: Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide (Abstract). Clinical Research 24: 141A (1976c).Google Scholar
- Williams, R.L.; Blaschke, T.F.; Meffin, P.J.; Melmon, K.L. and Rowland, M.: Antipyrine and indocyanine green as indicators of drug disposition during acute viral hepatitis (Abstract). Clinical Research 24: 259A (1976d).Google Scholar