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Interpretation of Drug Levels in Acute and Chronic Disease States

Clinical Pharmacokinetics volume 10, pages 498–513 (1985)Cite this article

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.

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References

  • Aldwin, L. and Kabakoff, D.: Metabolite interference in homogeneous enzyme-immunoassay of Phenytoin. Clinical Chemistry 27: 770–771 (1981).

    PubMed  CAS  Google Scholar 

  • Aronson, J.K.: Digoxin: Clinical aspects; in Richens and Marks (Eds) Therapeutic Drug Monitoring, pp. 404–414 (Churchill-Livingstone, Edinburgh 1980a).

    Google Scholar 

  • Aronson, J.K.: Clinical pharmacokinetics of digoxin. Clinical Pharmacokinelics 5: 137–149 (1980b).

    Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Bassey, H.I. and Hoffman, E.W.: A prospective evaluation of therapeutic drug monitoring. Therapeutic Drug Monitoring 5: 245–248 (1983).

    Article  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Bcnet, L.Z. (Ed.): The Effect of Disease States on Drug Kinetics (American Pharmaceutical Association, Washington D.C. 1976).

    Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Binnion, P.F. and Morgan, L.M.: Effect of acute hypokalemia on ‘H-digoxin metabolism. Cardiovascular Research 5: 431–435 (1971).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Chopra, D.: Janson, P. and Sawin, C.T.: lnscnsitivity to digoxin associated with hypocalcemia. New England Journal of Medicine 296: 917–918 (1977).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Drayer, D.E.: Active drug metabolites and renal failure. American Journal of Medicine 62: 486–489 (1977).

    PubMed  Article  CAS  Google Scholar 

  • Elin, R.J.: Discrepant results for the determination of theophylline in serum from a patient with renal failure. Clinical Chemistry 29: 1275 (1983).

    Google Scholar 

  • Elin, R.J. and Ruddell, M.: Discrepant results for determination of theophylline in serum of uremic patients. Clinical Chemistry 29: 1670 (1983).

    Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Gibson, T.P. and Nelson, A.H.: The question of digoxin metabolites in renal failure. Clinical Pharmacology and Therapeutics 27: 219–223 (1980).

    PubMed  Article  CAS  Google Scholar 

  • Graves, S.: Brown, B. and Valdes, R.: Digoxin-like substance in uremic patients: false positive effects on digoxin assays. Clinical Chemistry 29: 1166 (1983a).

    Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Green, L.H. and Smith, T.W.: The use of digitalis in patients with pulmonary disease. Annals of Internal Medicine 87: 459–465 (1977).

    PubMed  CAS  Google Scholar 

  • Griffiths, A., Hcbdigc, S.: Perucca, E. and Richens, A.: Quality control in drug measurement. Therapeutic Drug Monitoring 2: 51–59 (1980).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Guglcr, R. and Azarnoff, D.L.: Drug protein binding and the nephrotic syndrome. Clinical Pharmacokinetics 1: 25–35 (1976).

    Article  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    Google Scholar 

  • Jusko, W.J. and Weintraub, M.: Myocardial distribution of digoxin in renal failure. Clinical Pharmacology and Therapeutics 16: 449–454 (1974).

    PubMed  CAS  Google Scholar 

  • Koch-Weser, J.: Serum drug concentrations in clinical perspective; in Richens and Marks (Eds) Therapeutic Drug Monitoring, pp. 1–22 (Churchill-Livingstone, Edinburgh 1980).

    Google Scholar 

  • Koch-Weser, J.: Serum drug concentrations as therapeutic guides. New England Journal of Medicine 287: 227–231 (1972).

    PubMed  Article  CAS  Google Scholar 

  • Kumana, CR.: Therapeutic drug monitoring amidysrhythmic drugs: in Richens and Marks (Eds) Therapeutic Drug Monitoring, pp. 370–392 (Churchill-Livingstone, Edinburgh 1980).

    Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • McElnay, J.C. and D’Arcy, P.F.: Protein binding displacement interactions and their clinical importance. Drugs 25: 495–513 (1983).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    Google Scholar 

  • Morrison, J. and Killip, T.: Hypoxemia and digitalis toxicity in patients with chronic lung disease. Circulation 43–44 (Suppl. 2): 41 (1971).

    Google Scholar 

  • 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).

    Google Scholar 

  • Ochs, HR.: Greenblatt, D.J. and Woo, E.: Clinical pharmacokinetics of quinidine. Clinical Pharmacokinetics 5: 130–168 (1980).

    Article  Google Scholar 

  • Odar-Ccderlof, I.: Lunde, P. and Sjoqvist, F.: Abnormal pharmacokinetics of Phenytoin in a patient with uraemia. Lancet 2: 831–832 (1970).

    Article  Google Scholar 

  • Pape, B.E.: Enzyme immunoassay and two fluorometric methods compared for the determination of quinidine in serum. Therapeutic Drug Monitoring 3: 357–363 (1981).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Perucca, E.: Plasma protein binding of Phenytoin in health and disease: Relevance to therapeutic drug monitoring. Therapeutic Drug Monitoring 2: 331–344 (1980).

    PubMed  CAS  Google Scholar 

  • 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).

    Google Scholar 

  • 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).

    Google Scholar 

  • 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).

    Google Scholar 

  • Piafsky, K.M.: Disease-induced changes in the binding of basic drugs. Clinical Pharmacokinetics 5: 246–262 (1980).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Reidenberg, M.M. and Drayer, D.E.: Alteration of drug-protein binding in renal disease. Clinical Pharmacokinetics 9 (Suppl. 1): 18–26 (1984).

    PubMed  Article  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Richens, A. and Marks, V. (Eds): Therapeutic Drug Monitoring (Churchill-Livingstone, Edinburgh 1980).

    Google Scholar 

  • Richens, A. and Warrington, S.: When should plasma drug levels be monitored? Drugs 17: 488–500 (1979).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Shand, D.G.: α1-Acid glycoprotein and plasma lidocaine binding. Clinical Pharmacokinetics 9 (Suppl. 1): 27–31 (1984).

    PubMed  Article  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • Waddell, W.J. and Butler, T.C.: The distribution and excretion of phenobarbital. Journal of Clinical Investigation 36: 1217–1226 (1957).

    PubMed  Article  CAS  Google Scholar 

  • Weintraub, M.: Interpretation of the serum digoxin concentration. Clinical Pharmacokinetics 2: 205–219 (1977).

    PubMed  Article  CAS  Google Scholar 

  • 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).

    PubMed  Article  CAS  Google Scholar 

  • Yosselson-Superstine, S.: Drug interferences with plasma assays in therapeutic drug monitoring. Clinical Pharmacokinetics 9: 67–87 (1984).

    PubMed  Article  CAS  Google Scholar 

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  1. Department of Pharmacology and Therapeutics, University of Pavia, Piazza Botta, 10, 27100, Pavia, Italy

    Emilio Perucca, Roberto Grimaldi & Antonio Crema

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  1. Emilio Perucca
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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

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Keywords

  • Digoxin
  • Drug Level
  • Therapeutic Drug Monitoring
  • Clinical Pharmacokinetic
  • Lignocaine