Summary
Serum drug concentration monitoring can be an invaluable aid to patient management, particularly in certain pathological conditions when individualisation of dosage is particularly critical. To be clinically useful, however, drug levels must be interpreted in the context of all factors that could influence the correlation between the concentration of the drug in plasma and the intensity of action. Several such factors may be operating in acute and chronic diseuse states. For example, a number of pathological conditions are associated with marked changes in the fraction of free, pharmacologically active drug in plasma and this will result in disruption of the normal relationship between total serum drug level and effect, as seen for Phenytoin in uraemia. An altered response to a given serum drug level in disease states may also be caused by changes in tissue distribution, by abnormal accumulation of pharmacologically active metabolites in plasma or by changes in end-organ responsiveness. The latter are best illustrated by the altered sensitivity to digoxin in patients with various conditions, including hypokalemia and thyroid disease.
In addition to the factors listed above, consideration should also be given to potential interactions with concomitantly used drugs and to the possibility of analytical errors, especially in view of the evidence that the performance of otherwise reliable drug assays may be grossly impaired in certain diseases (e.g. uraemia), due to abnormal plasma composition and/or accumulation of interfering metabolites. In view of these complexities, a correct interpretation of serum drug levels requires a good knowledge of clinical pharmacology and a close collaboration between physician and laboratory. In any case, serum drug concentrations, like other laboratory tests, are not a substitute for careful patient observation, and any decision about drug treatment should be primarily based upon evaluation of the clinical state and, whenever possible, direct measurement of drug effects.
Similar content being viewed by others
References
Aldwin, L. and Kabakoff, D.: Metabolite interference in homogeneous enzyme-immunoassay of Phenytoin. Clinical Chemistry 27: 770–771 (1981).
Aronson, J.K.: Digoxin: Clinical aspects; in Richens and Marks (Eds) Therapeutic Drug Monitoring, pp. 404–414 (Churchill-Livingstone, Edinburgh 1980a).
Aronson, J.K.: Clinical pharmacokinetics of digoxin. Clinical Pharmacokinelics 5: 137–149 (1980b).
Aronson, J.K. and Grahame-Smith, D.G.: Altered distribution of digoxin in renal failure — a cause for digoxin toxicity? British Journal of Clinical Pharmacology 3: 1045–1051 (1976).
Aronson, J.K.: Grahame-Smith, D.G. and Wigley, F.M.: Monitoring digoxin therapy. The use of plasma digoxin concentration in the diagnosis of digoxin toxicity. Quarterly Journal of Medicine NS 47: 111–122 (1978).
Asconape, J.J. and Penry, J.K.: Use of amiepileplic drugs in the presence of liver and kidney diseases: A review. Epilepsia 23 (Suppl. 1): 565–579 (1982).
Atkinson Jr. A.J.: Stec, O.P.: Lertora, J.J.L.: Ruo, T.I. and Thenot, J.P.: Impact of active metabolites on monitoring plasma concentrations of therapeutic drugs. Therapeutic Drug Monitoring 2: 19–27 (1980).
Bassey, H.I. and Hoffman, E.W.: A prospective evaluation of therapeutic drug monitoring. Therapeutic Drug Monitoring 5: 245–248 (1983).
Baum, G.L.: Dick, M.M.: Blum, A.: KuA. and Carballo, J.: Factors involved in digitalis sensitivity in chronic pulmonary insufficiency. American Heart Journal 57: 460–462 (1959).
Beller, G.A.: Hood Jr. W.B.: Smith, T.W.: Abelman, W.H. and Wacker, J.P.: Correlation of serum magnesium and cardiologic digoxin intoxication. American Journal of Cardiology 33: 225–227 (1974).
Beller, G.A.: Smith, T.W. and Hood, W.B.: Altered distribution of titriated digoxin in the infarcted canine left ventricle. Circulation 46: 572–599 (1972).
Bcnet, L.Z. (Ed.): The Effect of Disease States on Drug Kinetics (American Pharmaceutical Association, Washington D.C. 1976).
Billing, Dahlqvist, R.: Garle, M: Hörnblad, Y. and Ripe, E.: Separate and combined use of theophylline in asthmatics. European Journal of Respiratory Diseases 63: 399–409 (1982).
Binnion, P.F. and Morgan, L.M.: Effect of acute hypokalemia on ‘H-digoxin metabolism. Cardiovascular Research 5: 431–435 (1971).
Blum, M.R.: Riegelman, S. and Becker, C.E.: Altered protein binding of diphenylhydantoin in uremic plasma. New England Journal of Medicine 286: 109 (1972).
Bower, J.O. and Mengle, H.A.K.: The additive effects of calcium and digitalis: a warning, with a report of two deaths. Journal of the American Medical Association 106: 1151–1153 (1936).
Bridges, R.R, and Jennison, T.A.: Spurious phenobarbital levels by fluorescence polarization immunoassay using TD analyzer in patients with renal disease. Therapeutic Drug Monitoring 6: 368–370 (1984).
Chopra, D.: Janson, P. and Sawin, C.T.: lnscnsitivity to digoxin associated with hypocalcemia. New England Journal of Medicine 296: 917–918 (1977).
Claguc, H.W.: Twum-Barima, Y. and Carruthers, G.: An audit of requests for therapeutic drug monitoring of digoxin: Problems and Pitfalls. Therapeutic Drug Monitoring 5: 249–254 (1983).
Danhof. M.: Hisaoka, M. and Levy, G.: Effect of experimental renal failure on the relationship between phenobarbital concentration and pharmacologie activity. II. World Conference on Clinical Pharmacology and Therapeutics, Washington D.C. 1983. Abstract 802, p. 138 (1983).
Drayer, D.E.: Active drug metabolites and renal failure. American Journal of Medicine 62: 486–489 (1977).
Drayer, D.E.: Active drug metabolites and renal failure. American Journal of Medicine 62: 486–489 (1977).
Elin, R.J.: Discrepant results for the determination of theophylline in serum from a patient with renal failure. Clinical Chemistry 29: 1275 (1983).
Elin, R.J. and Ruddell, M.: Discrepant results for determination of theophylline in serum of uremic patients. Clinical Chemistry 29: 1670 (1983).
EriH. S. and Calvo, R.: Postranslational changes of albumin as a cause of altered drug plasma protein binding; in Reidenberg and Erill (Eds) Drug Plasma Protein Binding (W.B. Saunders, Philadelphia; in press, 1985).
Galeazzi, R.L.: Pharmacodynamics and markers of drug effects. Therapeutic Drug Monitoring 2: 11–17 (1980).
Galeazzi, R.L.: Gugger, M. and Weidmann, P.: β-Blockade with pindolol. Differential cardiac and renal effects despite similar plasma kinetics in normal and uremic man. Kidney International 15: 661–668 (1979).
Giacomini, K.M. and Blaschke, T.F.: Effect of concentration-dependent binding to plasma proteins on the pharmacokinetics and pharmacodynamics of disopyramide. Clinical Pharmacokinetics 9 (Suppl. 1): 42–48 (1984).
Gianelly, R.: Von der Groeben, J.O.: Spivack, A.P. and Harrison, D.C.: Effect of lidocaine on ventricular arrhythmias in patients with coronary disease. New England Journal of Medicine 277: 1215–1219 (1967).
Gibson, T.P. and Nelson, A.H.: The question of digoxin metabolites in renal failure. Clinical Pharmacology and Therapeutics 27: 219–223 (1980).
Graves, S.: Brown, B. and Valdes, R.: Digoxin-like substance in uremic patients: false positive effects on digoxin assays. Clinical Chemistry 29: 1166 (1983a).
Graves, S.W.: Brown, B. and Valdes Jr. R.: Endogenous digoxin-like substance in patients with renal impairment. Annals of Internal Medicine 99: 604–608 (1983b).
Green, L.H. and Smith, T.W.: The use of digitalis in patients with pulmonary disease. Annals of Internal Medicine 87: 459–465 (1977).
Griffiths, A., Hcbdigc, S.: Perucca, E. and Richens, A.: Quality control in drug measurement. Therapeutic Drug Monitoring 2: 51–59 (1980).
Gugler, R.: Shocman, D.W.: Huffman, D.H.: Cohlmia, J.B. and Azarnoff, D.L.: Pharmacokinetics of drugs in patients with the nephrotic syndrome. Journal of Clinical Investigation 55: 1182–1189 (1975).
Guglcr, R. and Azarnoff, D.L.: Drug protein binding and the nephrotic syndrome. Clinical Pharmacokinetics 1: 25–35 (1976).
Halkin, H.: Meffin, P.: Melmon, K.L. and Rowland, M.: Influence of congestive heart failure on blood levels of lidocaine and its active monodiethylated metabolite. Clinical Pharmacology and Therapeutics 17: 669–676 (1975).
Harrison, C.E. and Wakim, K.G.: Inhibition of binding of triti-ated digoxin to myocardium by sodium depletion in dogs. Circulation Research 24: 263–268 (1969).
Holley, F.O.: Ponganis, K.V. and Slanski, D.R.: Effects of cardiac surgery with cardiopulmonary bypass on lidocaine disposition. Clinical Pharmacology and Therapeutics 35: 617–626 (1984).
Hopkins, B.E.: Taylor, R.R.: Henderson, C. and Burrows, P.: Digoxin distribution in the dog’s left ventricle in the presence of coronary artery ligation. Journal of Molecular and Cellular Cardiology 5: 197–203 (1973).
Jolley, M.E.: Stroupe, S.D.: Wang, C.H.J.: Panas, H.V.: Keegan, C.L. et al.: Fluorescence polarization immunoassay. I. Monitoring aminoglycoside antibiotics in serum and plasma. Clinical Chemistry 27: 1190–197 (1983).
Jusko, W.J. and Weintraub, M.: Myocardial distribution of digoxin in renal failure. Clinical Pharmacology and Therapeutics 16: 449–454 (1974).
Koch-Weser, J.: Serum drug concentrations in clinical perspective; in Richens and Marks (Eds) Therapeutic Drug Monitoring, pp. 1–22 (Churchill-Livingstone, Edinburgh 1980).
Koch-Weser, J.: Serum drug concentrations as therapeutic guides. New England Journal of Medicine 287: 227–231 (1972).
Kumana, CR.: Therapeutic drug monitoring amidysrhythmic drugs: in Richens and Marks (Eds) Therapeutic Drug Monitoring, pp. 370–392 (Churchill-Livingstone, Edinburgh 1980).
Letarte, L. and du Souich, P.: Influence of hypercapnia and/or hypoxemia and metabolite acidosis on theophylline kinetics in the conscious rabbit. American Review of Respiratory Diseases 129: 762–766 (1984).
Marcus, F.I.: Kapadia, G.G. and Goldsmith, C.: Alteration of the body distribution of tritiated digoxin by acute hyperkaliemia in the dog. Journal of Pharmacology and Experimental Therapeutics 165: 136–148 (1969).
McElnay, J.C. and D’Arcy, P.F.: Protein binding displacement interactions and their clinical importance. Drugs 25: 495–513 (1983).
McGowan, F.X.: Reiter, M.J.: Pritchett, L.C. and Shand, D.G.: Verapamil plasma binding: relationship to α1-acid glycoprotein and drug efficacy. Clinical Pharmacology and Therapeutics 33: 484–490 (1983).
Morrison, J. and Killip, T.: Hypoxemia and digitalis toxicity in patients with chronic lung disease. Circulation 43–44 (Suppl. 2): 41 (1971).
Nandedkar, A.: Williamson, R.: Kult, H. and Fairclough, G.F.: A comparison of plasma Phenytoin level determinations by EMIT and gas-liquid chromatography in patients with renal insufficiency. Therapeutic Drug Monitoring 4: 181–184 (1980).
Ochs, HR.: Greenblatt, D.J. and Woo, E.: Clinical pharmacokinetics of quinidine. Clinical Pharmacokinetics 5: 130–168 (1980).
Odar-Ccderlof, I.: Lunde, P. and Sjoqvist, F.: Abnormal pharmacokinetics of Phenytoin in a patient with uraemia. Lancet 2: 831–832 (1970).
Pape, B.E.: Enzyme immunoassay and two fluorometric methods compared for the determination of quinidine in serum. Therapeutic Drug Monitoring 3: 357–363 (1981).
Patel, J.A.: Clayton, L.T.: Le Bel, C.P. and McClatchey, K.D.: Abnormal theophylline levels in plasma by fluorescence polarization immunoassay in patients with renal disease. Therapeutic Drug Monitoring 6: 458–460 (1984).
Perucca, E.: Plasma protein binding of Phenytoin in health and disease: Relevance to therapeutic drug monitoring. Therapeutic Drug Monitoring 2: 331–344 (1980).
Perucca, A. and Richens, A.: Interpretation of drug levels: Relevance of plasma protein binding; in Drug Concentrations in Neuropsychiatry, pp. 52–68 (Excerpta Medica, Amsterdam 1980).
Perucca, E. and Richens, A.: Regulation and monitoring of drug therapy; in Williams and Marks (Eds) Biochemistry in Clinical Practice, pp. 379–399 (William Heinemann Medical Books Ltd, London 1983).
Perucca, E. and Richens, A.: Clinical pharmacokinetics of anti-epileptic drugs; in Frey and Janz (Eds) Antiepileptic Drugs, Handbook of Experimental Pharmacology. Vol. 74, pp. 661–723 (Springer-Verlag, Berlin 1985).
Piafsky, K.M.: Disease-induced changes in the binding of basic drugs. Clinical Pharmacokinetics 5: 246–262 (1980).
Piafsky, K.M.: Sitar, D.S.: Rangno, R.E. and Ogilvie, R.I.: Theophylline disposition in patients with hepatic cirrhosis. New England Journal of Medicine 296: 1495–1497 (1977).
Pieper, J.A.: Wygman, M.G.: Goldreyer, B.N.: Cannon, D.S.: Slaughter, R.L. and Lalka, D.: Lidocaine toxicity: Effects of total versus free lidocaine concentrations. (Abstract 690.) Circulation 62: 111–181 (1980).
Reidenberg, M.M. and Affrime, M.: Influence of disease on binding of drugs to plasma proteins. Annals of the New York Academy of Sciences 226: 115–126 (1973).
Reidenberg, M.M. and Drayer, D.E.: Alteration of drug-protein binding in renal disease. Clinical Pharmacokinetics 9 (Suppl. 1): 18–26 (1984).
Reynolds, F.: Ziroyanis, P.N.: Jones, N. and Smith, S.E.: Salivary Phenytoin concentrations in epilepsy and in chronic renal failure. Lancet 2: 384–386 (1976).
Richens, A. and Marks, V. (Eds): Therapeutic Drug Monitoring (Churchill-Livingstone, Edinburgh 1980).
Richens, A. and Warrington, S.: When should plasma drug levels be monitored? Drugs 17: 488–500 (1979).
Routledge, P.A.: Stargel, W.W.: Barchowsky, A.: Wagner, G.S. and Shand, D.: Control of lidocaine therapy: New perspectives. Therapeutic Drug Monitoring 4: 265–270 (1982).
Sawchuk, R.J. and Matzke, G.R.: Contribution of 5-(4-hydroxy-phenyl)-5-phenylhydanloin to the discrepancy between phen-ytoin analyses by EMIT and high-pressure liquid chromatography. Therapeutic Drug Monitoring 6: 97–103 (1984).
Shand, D.G.: α1-Acid glycoprotein and plasma lidocaine binding. Clinical Pharmacokinetics 9 (Suppl. 1): 27–31 (1984).
Sirgo, M.A.: Green, P.J.: Rocci, M.L. and Vlasses, P.H.: Interpretation of serum Phenytoin concentrations in uremia in assay-dependent. Neurology 34: 1250–1251 (1984).
du Souich, P.: Clozel, J.P.: Saunier, Hartemann. D.: Schrijven. F. and Amend, P.: The influence of hypoxemia on digoxin plasma kinetics and tissue distribution in conscious dog. American Review of Respiratory Diseases (In press 1985b).
du Souich, P.: Clozel, J.P.: Saunier, L.: Long, H.: Hartemann, D. et al.: Influence of hypoxemia and respiratory acidosis on the plasma kinetics and tissue distribution of digoxin in the conscious dog. Canadian Journal of Physiology and Pharmacology (In press 1985a).
du Souich. P. and Erill. S.: Metabolism of procaine and procainamide in patients with hepatic disease. Clinical Pharmacology and Therapeutics (1976).
Storstein, L.: Protein binding of cardiac glycosides in disease states. Clinical Pharmacokinetics 2: 220–233 (1977).
Toseland, P.A.: Wicks, J.F.C. and Newall, R.G.: Application of substrate-labelled fluorescent immunoassay to the measurement of anticonvulsant and antiasthmatic drug levels in plasma and serum. Therapeutic Drug Monitoring 5: 501–504 (1983).
Verbeeck, R.K.: Branch, R.A. and Wilkinson, G.A.: Drug metabolites in renal failure: Pharmacokinetic and clinical implications. Clinical Pharmacokinetic 6: 329–345 (1981).
Waddell, W.J. and Butler, T.C.: The distribution and excretion of phenobarbital. Journal of Clinical Investigation 36: 1217–1226 (1957).
Weintraub, M.: Interpretation of the serum digoxin concentration. Clinical Pharmacokinetics 2: 205–219 (1977).
Yacobi, A. and Levy, G.: Intraindividual relationship between serum protein binding of drugs in normal human subjects, patients with impaired renal function, and rats. Journal of Pharmaceutical Sciences 66: 1285–1288 (1977).
Yosselson-Superstine, S.: Drug interferences with plasma assays in therapeutic drug monitoring. Clinical Pharmacokinetics 9: 67–87 (1984).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Perucca, E., Grimaldi, R. & Crema, A. Interpretation of Drug Levels in Acute and Chronic Disease States. Clin Pharmacokinet 10, 498–513 (1985). https://doi.org/10.2165/00003088-198510060-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-198510060-00003