Clinical Pharmacokinetics

, Volume 20, Issue 6, pp 429–446 | Cite as

Nonlinear Pharmacokinetics

Clinical Implications
  • Thomas M. Ludden
Review Article Drug Disposition


Nonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. One of the more important sources of nonlinearity is the partial saturation of presystemic metabolism exhibited by such drugs as verapamil, propranolol and hydralazine. In such cases, circulating drug concentrations are sensitive not only to dose size but also to rate of absorption: slower absorption may decrease the overall systemic availability.

The binding of drugs to plasma constituents, blood cells and extravascular tissue may exhibit concentration dependence. This can cause pharmacokinetic parameters based on total blood or serum drug concentrations to be concentration-dependent. Often, in these cases, parameters based on free drug concentration appear linear. An important consideration in regard to concentration-dependent serum binding is the difficulty in relating total concentration to a usual therapeutic range if free concentration is a better indicator of drug effect. Measurement of free concentration is needed in these cases, particularly if the intersubject variability in binding is high. An example of this behaviour is valproic acid.

Partial saturation of elimination pathways can result in the well known behaviour typical of Michaelis-Menten pharmacokinetics. Small changes in dosing rate can make much larger differences in steady-state concentration. The time to achieve a given fraction of steady-state becomes longer as the dosing rate approaches the maximum elimination rate. Alcohol and phenytoin are examples of drugs that exhibit such behaviour. The sensitivity of steady-state concentration and cumulation rate to changes in dosing rate are both influenced by the magnitude of parallel firstorder elimination pathways: even a first-order pathway that is only 1 to 2% of maximum clearance (which occurs at very low concentration) can be an important determinant of steady-state concentration and cumulation rate when concentrations are high. Theophylline and salicylate have significant parallel first-order elimination pathways as well as saturable pathways.

Autoinduction causes an increase in clearance with long term administration. In some cases, dosage adjustment must be made to compensate for the increase, and the possibility that the degree of induction may be dose- or concentration-dependent must be kept in mind. Carbamazepine is a major example of autoinduction.

It is fortunate that only a few of the many hundreds of drugs in use exhibit nonlinear behaviour that leads to clinical implications. An understanding of the causes of nonlinearity and the influence of such behaviour on concentration-time profiles is required if such drugs are to be used safely and efficaciously.


Clinical Pharmacology Plasma Protein Binding Disopyramide Free Drug Concentration Salicylamide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abramson FP. Kinetic models of induction: 1. Persistence of the inducing substance. Journal of Pharmaceutical Sciences 75: 223–228, 1986PubMedCrossRefGoogle Scholar
  2. Acocella G, Nattiussi R, Segre G. Multicompartmental analysis of serum, urine and bile concentrations of rifampicin and desacetyl-rifampicin in subjects treated for one week. Pharmacological Research Communications 10: 271–288, 1978PubMedCrossRefGoogle Scholar
  3. Acocella G, Pangani V, Narchetti M, Baroni GC, Nicolis FB. Kinetic studies on rifampicin: I. Serum concentration analysis in subjects treated with different oral doses over a period of two weeks. Chemotherapy 16: 356–370, 1971PubMedCrossRefGoogle Scholar
  4. Barchowsky A, Shand DG, Stargel WW, Wagner GS, Routledge PA. On the role of α-acid glycoprotein in lignocaine accumulation following myocardial infarction. British Journal of Clinical Pharmacology 13: 411–415, 1982PubMedCrossRefGoogle Scholar
  5. Barrett WE, Bianchine JR. The bioavailability of ultramicronized griseofulvin (GRIS-PEG®) tablets in man. Current Therapeutic Research 18: 501–509, 1975PubMedGoogle Scholar
  6. Bauer LA, Blouin RA. Phenytoin Michaelis-Menten pharmacokinetics in Causasian paediatric patients. Clinical Pharmacokinetics 8: 545–549, 1983PubMedCrossRefGoogle Scholar
  7. Bauer LA, Brown T, Gibaldi M, Hudson L, Nelson S, et al. Influence of long-term infusions on lidocaine kinetics. Clinical Pharmacology and Therapeutics 31: 433–437, 1982PubMedCrossRefGoogle Scholar
  8. Bauer LA, Davis R, Wilensky A, Raisys V, Levy RH. Valproic acid clearance: unbound fraction and diurnal variation in young and elderly adults. Clinical Pharmacology and Therapeutics 37: 697–700, 1985PubMedCrossRefGoogle Scholar
  9. Bax NDS, Tucker GT, Woods HF. Lignocaine and indocyanine green kinetics in patients following myocardial infarction. British Journal of Clinical Pharmacology 10: 353–361, 1980PubMedGoogle Scholar
  10. Bertilsson L, Höjer B, Tybring G, Osterloh J, Rane A. Autoinduction of carbamazepine metabolism in children examined by a stalle isotope technique. Clinical Pharmacology and Therapeutics 27: 83–88, 1980PubMedCrossRefGoogle Scholar
  11. Bianchine JR, Calimlim LR, Morgan JP, Dujouve, Lasagna L. Metabolism and absorption of L-3,4-dihydroxy-phenylalanine in patients with Parkinson’s disease. Annals of the New York Academy of Sciences 179: 126–140, 1971PubMedCrossRefGoogle Scholar
  12. Boucher BA, Rodman JH, Fabian TC, Cupit GC, Ludden TM, et al. Disposition of Phenytoin in critically ill trauma patients. Clinical Pharmacy 6: 881–887, 1987PubMedGoogle Scholar
  13. Boucher BA, Rodman JH, Jaresko GS, Rasmussin SN, Watridge CB, et al. Phenytoin pharmacokinetics in critically ill trauma patients. Clinical Pharmacology and Therapeutics 44: 675–683, 1988PubMedCrossRefGoogle Scholar
  14. Bowdle TA, Patel IH, Levy RH, Wilensky AJ. Valproic acid dosage and plasma protein binding and clearance. Clinical Pharmacology and Therapeutics 28: 486–492, 1980PubMedCrossRefGoogle Scholar
  15. Butcher MA, Frazer LA, Reddel HD, Marlin GE. Dose-dependent pharmacokinetics with single daily dose slow release theophylline in patients with chronic lung disease. British Journal of Clinical Pharmacology 13: 241–243, 1982PubMedCrossRefGoogle Scholar
  16. Buylaert WA, Herregods LL, Mortier EP, Bogaert MG. Cardiopulmonary bypass and the pharmacokinetics of drugs: an update. Clinical Pharmacokinetics 17: 10–26, 1989PubMedCrossRefGoogle Scholar
  17. Byrne AJ, McNeil JJ, Harrison CM, Louis W, Tonkin AM, et al. Stable oral availability of sustained release propranolol when co-administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions. British Journal of Clinical Pharmacology 17: 45S–0S, 1984PubMedCrossRefGoogle Scholar
  18. Cramer JA, Mattson RH, Bennett DM, Swick CT. Variable free and total valproic acid concentrations in sole- and multi-drug therapy. Therapeutic Drug Monitoring 8: 411–415, 1986PubMedCrossRefGoogle Scholar
  19. Crawford MH, Ludden TM, Kennedy GT. Determinants of systemic availability of oral hydralazine in heart failure. Clinical Pharmacology and Therapeutics 38: 538–543, 1985PubMedCrossRefGoogle Scholar
  20. Crowley JJ, Koup JR, Cusack BJ, Ludden TM, Vestel RE. Evaluation of a proposed method for Phenytoin maintenance dose prediction following an intravenous loading dose. European Journal of Clinical Pharmacology 32: 141–148, 1987PubMedCrossRefGoogle Scholar
  21. Davies RF, Dube LM, Mousseau N. Perioperative variability of binding of lidocaine, quinidine, and propranolol after cardiac operations. Journal of Thoracic and Cardiovascular Surgery 96: 634–641, 1988PubMedGoogle Scholar
  22. Day RO, Shi DD, Azarnoff DL. Induction of salicyluric acid formation in rheumatoid arthritis patients treated with salicylates. Clinical Pharmacokinetics 8: 263–271, 1983PubMedCrossRefGoogle Scholar
  23. Drucker MM, Blondheim SJ, Wislicki L. Factors affecting acetyl-ation in vivo of para-aminobenzoic acid by human subjects. Clinical Science 27: 133–141, 1964PubMedGoogle Scholar
  24. Dvornik D, Kraml M, Dubuc J, Fencik M, Weidler D, et al. Propranolol concentrations in healthy men given 80mg daily in divided doses: effect of food and circadian variation. Current Therapeutic Research 32: 214–224, 1982Google Scholar
  25. Eichelbaum M, Mikus G, Vogelgesang B. Pharmacokinetics of (+), (−) and (±) verapamil after intravenous administration. British Journal of Clinical Pharmacology 17: 453–458, 1984PubMedCrossRefGoogle Scholar
  26. Fleckenstein L, Mundy GR, Horovitz RA, Mazzullo JM. Sodium salicylamide: relative bioavailability and subjective effects. Clinical Pharmacology and Therapeutics 19: 451–458, 1976PubMedGoogle Scholar
  27. Freedman SB, Richmond DR, Ashley JJ, Kelly DT. Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clinical Pharmacology and Therapeutics 30: 644–652, 1981PubMedCrossRefGoogle Scholar
  28. Furst DE, Gupta N, Paulus HE. Salicylate metabolism in twins: evidence suggesting a genetic influence and induction of salicylurate formation. Journal of Clinical Investigation 60: 32–41, 1977PubMedCrossRefGoogle Scholar
  29. Furst DE, Tozer TN, Melmon KL. Salicylate clearance: the result of protein binding and metabolism. Clinical Pharmacology and Therapeutics 26: 380–389, 1979PubMedGoogle Scholar
  30. Gelboin HV. Mechanisms of induction of drug-metabolizing enzymes. In Brodie & Gillette (Eds) Concepts in biochemical pharmacology, Handbuch der Experiementellen Pharmacologie, Vol. 28, Part 2, Springer-Verlag, New York, 1971Google Scholar
  31. Gelehrter TD. Enzyme induction. New England Journal of Medicine 294: 522–526, 589-595, 646-651, 1976PubMedCrossRefGoogle Scholar
  32. George CF. Drug metabolism by the gastrointestinal mucosa. Clinical Pharmacokinetics 6: 259–274, 1981PubMedCrossRefGoogle Scholar
  33. Gerardin AP, Abadie FV, Campestrini JA, Theobald W. Pharmacokinetics of carbamazepine in normal humans after single and repeated oral doses. Journal of Pharmacokinetics and Biopharmaceutics 4: 521–535, 1976Google Scholar
  34. Giacomini KM, Nelson WL, Pershe A, Valdivieso L, Turner-Tamiasu K, et al. In vivo interactions of the enantiomers of disopyramide in human subjects. Journal of Pharmacokinetics and Biopharmaceutics 14: 335–356, 1986PubMedGoogle Scholar
  35. Giacomini KM, Swezey SE, Turner-Tamiyasu K, Blaschke TF. The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide. Journal of Pharmacokinetics and Biopharmaceutics 10: 1–14, 1982PubMedGoogle Scholar
  36. Gibaldi M, Koup JR. Pharmacokinetic concepts: drug binding, apparent volume of distribution and clearance. European Journal of Clinical Pharmacology 20: 299–305, 1981PubMedCrossRefGoogle Scholar
  37. Gibaldi M, McNamara PJ. Apparent volumes of distribution and drug binding to plasma proteins and tissue. European Journal of Clinical Pharmacology 13: 373–378, 1978PubMedCrossRefGoogle Scholar
  38. Gillespie NG, Mena J, Cotzias GC, Bell MA. Diets affecting treatment of parkinsonism with levodopa. Journal of the American Diet Association 62: 525–528, 1973Google Scholar
  39. Ginchansky E, Weinberger M. Relationship of theophylline clearance to oral dosage in children with chronic asthma. Journal of Pediatrics 91: 655–660, 1977PubMedCrossRefGoogle Scholar
  40. Godley PJ, Hawley LL, Ludden TM, Rasmussen RJ. A nonsteady-state Phenytoin prediction program that includes drug interaction parameter modifiers. Clinical Pharmacology and Therapeutics 47: 183, 1990Google Scholar
  41. Godley PJ, Ludden TM, Clementi WA, Godley SE, Ramsey RR. Evaluation of a Bayesian regression analysis computer program using nonsteady-state Phenytoin concentrations. Clinical Pharmacy 6: 634–639, 1987PubMedGoogle Scholar
  42. Gonzalez FJ, Skoda R, Hardwick JP, Song BJ, Umeno M, et al. Human and rat debrisoquine hydroxylase and ethanol-inducible P-450 gene families: structure regulation and polymorphisms. In Miners et al. (Eds) Microsomes and drug oxidations, pp. 209–215, Taylor and Francis, London, 1988Google Scholar
  43. Gram L, Flachs H, Wurty-Jorgensen A, Parnas J, Andersen B. Soldium valproate, relationship between serum levels and therapeutic effect: a controlled study. In Johennessen et al. (Eds) Antiepileptic therapy: advances in drug monitoring, pp. 247–252, Raven Press, New York, 1980Google Scholar
  44. Granerus AK, Jagenburg R, Rodjer S, Svanborg A. Phenyalanine absorption and metabolism in Parkinsonian patients. British Medical Journal 4: 262–264, 1971PubMedCrossRefGoogle Scholar
  45. Grasela TH, Sheiner LB, Rambeck B, et al. Steady-state pharmacokinetics of Phenytoin from routinely collected patient data. Clinical Pharmacokinetics 8: 355–364, 1983PubMedCrossRefGoogle Scholar
  46. Haughey DB, Kraft CJ. Disopyramide protein binding and alpha1 acid glycoprotein concentrations in serum obtained from kidney transplant recipients. Clinical Pharmacokinetics 9 (Suppl. 1): 97–98, 1984CrossRefGoogle Scholar
  47. Hinderling PH, Garrett ER. Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans. Journal of Pharmacokinetics and Biopharmaceutics 4: 199–230, 1976PubMedGoogle Scholar
  48. Hoffman WS, Nobe C. The influence of urinary pH on the renal excretion of salicyl derivatives during aspirin therapy. Journal of Laboratory and Clinical Medicine 35: 237–248, 1950PubMedGoogle Scholar
  49. Jenne JW, Wyze E, Rood FS, McDonald FM. Pharmacokinetics of theophylline: application to adjustment of the clinical dose of aminophylline. Clinical Pharmacology and Therapeutics 13: 349–360, 1972PubMedGoogle Scholar
  50. Jung D, Powell JR, Walson C, Perrier D. Effect of dose on Phenytoin absorption. Clinical Pharmacology and Therapeutics 28: 479–485, 1980PubMedCrossRefGoogle Scholar
  51. Killilea T, Coleman R, Ludden T, Peck CC, Rose D. Bayesian regression analysis of nonsteady-state Phenytoin concentrations: evaluation of predictive performance. Therapeutic Drug Monitoring 11: 455–462, 1989PubMedGoogle Scholar
  52. Kimura T, Yamamoto T, Mizuno M, Suga Y, Kitade S, et al. Characterization of aminocephalosporin transport across rat small intestine. Journal of Pharmacokinetics and Biodynamics 6: 246–253, 1983CrossRefGoogle Scholar
  53. Koup JR, Williams-Warren J, Weber A, Smith AL. Pharmacokinetics of rifampin in children: I. Multiple dose intravenous infusion. Therapeutic Drug Monitoring 8: 11–16, 1986PubMedCrossRefGoogle Scholar
  54. Legg B, Rowland M. Saturable binding of cyclosporin A to erythrocytes: estimation of binding parameters in renal transplant patients and implications for bioavailability assessment. Pharmaceutical Research 5: 80–85, 1988PubMedCrossRefGoogle Scholar
  55. LeLorier J, Grenon D, Latour Y, Caillé G, Dumont G, et al. Pharmacokinetics of lidocaine after prolonged intravenous infusion in uncomplicated myocardial infarction. Annals of Internal Medicine 87: 700–702, 1977aPubMedGoogle Scholar
  56. LeLorier L, Morgan R, Gagne J, Caillé G. Effect of duration of infusion on the disposition of lidocaine in dogs. Journal of Pharmacology and Experimental Therapeutics 203: 507–511, 1977bPubMedGoogle Scholar
  57. Lesko LJ. Nonlinear kinetics and theophylline elimination. In Benet et al. (Eds) Pharmacokinetic basis for drug treatment, pp. 321–332, Raven Press, New York, 1984Google Scholar
  58. Levy G. Pharmacokinetics of salicylate elimination in man. Journal of Pharmaceutical Sciences 54: 959–967, 1965PubMedCrossRefGoogle Scholar
  59. Levy G, Jusko WJ. Factors affecting the absorption of riboflavin in man. Journal of Pharmaceutical Sciences 55: 285–289, 1966PubMedCrossRefGoogle Scholar
  60. Levy G, Matsuzawa T. Pharmacokinetics of salicylamide in man. Journal of Pharmacology and Experimental Therapeutics 156: 285–293, 1967PubMedGoogle Scholar
  61. Levy G, Tsuchiya T. Salicylate accumulation kinetics in man. New England Journal of Medicine 287: 430–432, 1972PubMedCrossRefGoogle Scholar
  62. Levy RH, Dumain MS, Cook JL. Time-dependent kinetics: V. Time course of drug levels during enzyme induction (one-compartment model). Journal of Pharmacokinetics and Biopharmaceutics 7: 557–578, 1979PubMedGoogle Scholar
  63. Li T-K, Bosron WF, Dafeldecker WP, Lange LG, Vallee BL. Isolation of 7r-alcohol dehydrogenase of human liver: Is it a determinant of alcoholism? Proceedings of the National Academy of Science USA 74: 4378–4381, 1977CrossRefGoogle Scholar
  64. Lieber CS, DeCarli LM. The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo. Journal of Pharmacology and Experimental Therapeutics 181: 279–287, 1972PubMedGoogle Scholar
  65. Lima JJ. Interaction of disopyramide enantiomers for sites on plasma proteins. Life Science 41: 2801–2813, 1988Google Scholar
  66. Lima JJ, Boudoulas H. Stereoselective effects of disopyramide enantiomers in humans. Journal of Cardiovascular Pharmacology 9: 594–600, 1987PubMedCrossRefGoogle Scholar
  67. Lima JJ, Boudoulas H, Blanford BF. Concentration-dependence of disopyramide binding to serum protein and its influence on kinetics and dynamics. Journal of Pharmacology and Experimental Therapeutics 219: 741–747, 1981PubMedGoogle Scholar
  68. Lima JJ, Boudoulas H, Shields BJ. Stereoselective pharmacokinetics of disopyramide in man. Drug Metabolism and Disposition 13: 572–577, 1985PubMedGoogle Scholar
  69. Lima JJ, Haughey DB, Leier CV. Disopyramide pharmacokinetics and bioavailability following simultaneous administration of disopyramide and 14C-disopyramide. Journal of Pharmacokinetics and Biopharmaceutics 12: 289–313, 1984bPubMedGoogle Scholar
  70. Lima JJ, Jungbluth G, Devine E, Robertson L. Stereoselective binding of disopyramide to human plasma proteins. Life Science 35: 835–839, 1984aCrossRefGoogle Scholar
  71. Lima JJ, Wenzke SC, Boudoulas H, Schaal SF. Antiarrhythmic activity and unbound concentrations of disopyramide enantiomers in patients. Therapeutic Drug Monitoring 12: 23–28, 1990PubMedCrossRefGoogle Scholar
  72. Ludden TM. Anticonvulsants. In Williams et al. (Eds) Rational therapeutics, chapter 21, pp. 579–609, Marcel Dekker, New York, 1990Google Scholar
  73. Ludden TM, Allen JP, Schneider LW, Stavchansky SA. Rate of Phenytoin accumulation in man: a simulation study. Journal of Pharmacokinetics and Biopharmaceutics 6: 399–415, 1978PubMedGoogle Scholar
  74. Ludden TM, Rotenberg KS, Ludden LK, Shepherd AMM, Woodworth JR. Relative bioavailability of immediate and sustained-release hydralazine formulations. Journal of Pharmaceutical Sciences 7: 1026–1032, 1988CrossRefGoogle Scholar
  75. Marlin GE, Butcher MA, Klumpp JA, Thompson PJ. Pharmacokinetics of a single evening dose of slow-release theophylline in patients with chronic lung disease. British Journal of Clinical Pharmacology 12: 443–445, 1981PubMedCrossRefGoogle Scholar
  76. Martis L, Levy RH. Bioavailability calculations for drugs showing simultaneous first-order and capacity-limited elimination kinetics. Journal of Pharmacokinetics and Biopharmaceutics 1: 283–294, 1973Google Scholar
  77. Mawer GE, Mullen P, Rogers M, Robinson AJ, Lucas SD. Phenytoin dose adjustment in epileptic patients. British Journal of Clinical Pharmacology 1: 163–168, 1974PubMedCrossRefGoogle Scholar
  78. Mayersohn M. Ascorbic acid absorption in man — pharmacokinetic implications. European Journal of Pharmacology 19: 140–142, 1972PubMedCrossRefGoogle Scholar
  79. Mayersohn M. Principles of drug absorption. In Banker & Rhodes (Eds) Drugs and the pharmaceutical sciences, Vol. 40, Modern Pharmaceutics, 2nd ed., pp. 22–89, Marcel Dekker, Inc., New York, 1990Google Scholar
  80. McAinsh J, Baber NS, Holmes BF, Young J, Ellis LH. Bioavailability of sustained release propranolol formulation. Biopharmaceutics and Drug Disposition 2: 39–48, 1981CrossRefGoogle Scholar
  81. McAinsh J, Baber NS, Smith R, Young J. Pharmacokinetic and pharmacodynamic studies with long-acting propranolol. British Journal of Clinical Pharmacology 6: 115–121, 1978PubMedCrossRefGoogle Scholar
  82. McAinsh J, Gay MA. Theoretical Michaelis-Menten elimination model for propranolol. European Journal of Drug Metabolism and Pharmacokinetics 10: 241–245, 1985PubMedCrossRefGoogle Scholar
  83. McLean AJ, McNamara PJ, duSouich P, Gibaldi M, Lalka D. Food, splanchnic blood flow and bioavailability of drugs subject to first-pass metabolism. Clinical Pharmacology and Therapeutics 24: 5–10, 1978PubMedGoogle Scholar
  84. McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction between oral propranolol and hydralazine. Clinical Pharmacology and Therapeutics 27: 726–732, 1980PubMedCrossRefGoogle Scholar
  85. McNamara PJ, Colburn WA, Gibaldi M. Time course of carbamazepine self-induction. Journal of Pharmacokinetics and Biopharmaceutics 7: 63–68, 1979PubMedGoogle Scholar
  86. Meffin PJ, Robert EW, Winkle RA. Role of concentration dependent binding in disopyramide disposition. Journal of Pharmacokinetics and Biopharmaceutics 7: 29–46, 1979PubMedGoogle Scholar
  87. Miner DJ, Kissinger PT. Evidence for the involvement of N-acetyl-p-quinoneimine in acetaminophen metabolism. Biochemical Pharmacology 28: 3285–3290, 1979PubMedCrossRefGoogle Scholar
  88. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow JD, Keiser H. Acetaminophen-induced hepatic injury: protective role for glutathione in man and rationale for therapy. Clinical Pharmacology and Therapeutics 16: 676–684, 1974PubMedGoogle Scholar
  89. Monks TJ, Caldwell J, Smith RL. Influence of methylanthinecontaining floods on theophylline metabolism and kinetics. Clinical Pharmacology and Therapeutics 26: 513–524, 1979PubMedGoogle Scholar
  90. Morgan DJ, Smallwood RA. Clinical significance of pharmacokinetic models of hepatic elimination. Clinical Pharmacokinetics 18: 61–76, 1990PubMedCrossRefGoogle Scholar
  91. Ochs HR, Carstens G, Greenblatt DJ. Reduction in lidocaine clearance during continuous infusion and by coadministration of propranolol. New England Journal of Medicine 303: 373–377, 1980PubMedCrossRefGoogle Scholar
  92. Oellerich M, Müller-Vahl H. The EMIT free level ultrafiltration technique compared with equilibrium dialysis and ultracentrifugation to determine protein binding of Phenytoin. Clinical Pharmacokinetics 9 (Suppl. 1): 61–70, 1984PubMedCrossRefGoogle Scholar
  93. Øie S, Guentert TW, Tozer TN. Effect of saturable binding on the pharmacokinetics of drugs: a simulation. Journal of Pharmacy and Pharmacology 32: 471–477, 1980PubMedCrossRefGoogle Scholar
  94. Øie S, Tozer TN. Effect of altered plasma protein binding on apparent volume of distribution. Journal of Pharmaceutical Sciences 68: 1203–1205, 1979PubMedCrossRefGoogle Scholar
  95. O’Reilly RA, Aggeler PM, Leong LS. Studies on the coumarin anticoagulant drugs: a comparison of the pharmacodynamics of lucimarol and warfarin in man. Thrombosis Diathesis Haemorrhagica 11: 1–22, 1964Google Scholar
  96. Pancorbo S, Benson J, Goetz D, Moore K, Valida A, et al. Evaluation of the effect of a nonlinear kinetics on dosage adjustments of theophylline. Therapeutic Drug Monitoring 5: 173–177, 1983PubMedCrossRefGoogle Scholar
  97. Perrier D, Ashley JJ, Levy G. Effect of product inhibition on kinetics of duty elimination. Journal of Pharmacokinetics and Biopharmaceutics 1: 231–242, 1973Google Scholar
  98. Piafsky KM, Borgå O, Odar-Cederlöf I, Johansson C, Sjöqvist F. Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α-acid glycoprotein. New England Journal of Medicine 299: 1436–1439, 1978CrossRefGoogle Scholar
  99. Pitlick WH, Levy RH, Troupin AS, Green JR. Pharmacokinetic model to describe self-induced decreases in steady-state concentration of carbamazepine. Journal of Pharmaceutical Sciences 65: 462–463, 1976PubMedCrossRefGoogle Scholar
  100. Pond SM, Tozer TN. First-pass elimination: basic concepts and clinical consequences. Clinical Pharmacokinetics 9: 1–25, 1984PubMedCrossRefGoogle Scholar
  101. Prescott LF. Paracetamol overdosage: pharmacological considerations and clinical management. Drugs 25: 290–314, 1983PubMedCrossRefGoogle Scholar
  102. Prescott LF, Adjeponyamoach KK, Talbot RG. Impaired lignocaine metabolism in patients with myocardial infarction and cardiac failure. British Medical Journal 1: 939–941, 1976PubMedCrossRefGoogle Scholar
  103. Privitera MD, Homan RW, Ludden TM, Peck CC, Vasko MR. Clinical utility of a Bayesian dosing program for Phenytoin. Therapeutic Drug Monitoring 11: 285–295, 1989PubMedCrossRefGoogle Scholar
  104. Pynnönen S, Frey H, Sillanpää. The auto-induction of carbamazepine during long-term therapy. International Journal of Clinical Pharmacology, Therapeutics and Toxicology 18: 247–252, 1980Google Scholar
  105. Reidenberg MM, Drayer D, de Marco AL, Bello CT. Hydralazine elimination in man. Clinical Pharmacology and Therapeutics 14: 970–977, 1973PubMedGoogle Scholar
  106. Reigner BG, Covet W, Guedes J-P, Fourtillan J-B, Tozer TN. Saturable rate of cefatrizine absorption after oral administration to humans. Journal of Pharmacokinetics and Biopharmaceutics 18: 17–34, 1990PubMedGoogle Scholar
  107. Riva R, Albani F, Franzoni E, Perucca E, Santucci M, et al. Valproic acid free fraction in epileptic children under chronic monotherapy. Therapeutic Drug Monitoring 5: 197–200, 1983PubMedCrossRefGoogle Scholar
  108. Robinson PJ, Bass L, Pond SM, Roberts MS, Wagner JG. Clinical applicability of current pharmacokinetic models: splanchnic elimination of 5-fluorouracil in cancer patients. Journal of Pharmacokinetics and Biopharmaceutics 16: 229–249, 1988PubMedGoogle Scholar
  109. Routledge PA, Barchowsky A, Bjornssen TD, Kitchell BB, Shand DG. Lidocaine plasma protein binding. Clinical Pharmacology and Therapeutics 27: 347–351, 1980aPubMedCrossRefGoogle Scholar
  110. Routledge PA, Shand DG, Barchowsky A, Wagner G, Stargell WW. Relationship between alpha-acid glycoprotein and lidocaine disposition in myocardial infarction. Clinical Pharmacology and Therapeutics 30: 154–157, 1981PubMedCrossRefGoogle Scholar
  111. Routledge PA, Stargel WW, Barchowsky A, Wagner GS, Shand DG. Factors affecting free (unbound) lignocaine concentration in suspected acute myocardial infarction. British Journal of Clinical Pharmacology 28: 593–597, 1989PubMedCrossRefGoogle Scholar
  112. Routledge PA, Stargel WW, Wagner GS, Shand DG. Increased α1-acid glycoprotein and lidocaine disposition in myocardial infarction. Annals of Internal Medicine 93: 701–704, 1980bPubMedGoogle Scholar
  113. Rowland M, Tozer TN. Dose and time dependencies in clinical pharmacokinetics: concepts and applications, 2nd ed., chapter 22, pp. 376–400, Lea & Febiger, Philadelphia, 1989Google Scholar
  114. Rumble RH, Brooks LPM, Roberts MS. Metabolism of salicylate during chronic aspirin therapy. British Journal of Clinical Pharmacology 9: 41–45, 1980PubMedCrossRefGoogle Scholar
  115. Sarrazin E, Hendeles L, Weinberger M, Muir K, Riegelman S. Dose-dependent kinetics for theophylline: observations among ambulatory asthmatic children. Journal of Pediatrics 97: 825–828, 1980PubMedCrossRefGoogle Scholar
  116. Scheyer RD. Bayesian non steady state phenytoin predictions: effect of parallel elimination pathways. Clinical Pharmacology and Therapeutics 47: 156, 1990Google Scholar
  117. Scheyer RD, Cramer JA, Toftness BR, Hochholzer JM, Mattson RH. In vivo determination of valproate binding constants during sole and multi-drug therapy. Therapeutic Drug Monitoring 12: 117–123, 1990PubMedCrossRefGoogle Scholar
  118. Sedman AJ, Wagner JG. Quantitative pooling of Michaelis-Menten equations in models with parallel metabolite formation paths. Journal of Pharmacokinetics and Biopharmaceutics 2: 149–160, 1974PubMedGoogle Scholar
  119. Shand DG, Hammill SC, Aarronsen L, Pritchett ELC. Reduced verapamil clearance during long term oral administration. Clinical Pharmacology and Therapeutics 30: 701–703, 1981PubMedCrossRefGoogle Scholar
  120. Shen DD, Fixley M, Azarnoff DL. Theophylline bioavailability following chronic dosing of an elixer and two solid dosage forms. Journal of Pharmaceutical Sciences 67: 916–919, 1978PubMedCrossRefGoogle Scholar
  121. Shepherd AMM, Irving NA, Ludden TM, Lin MS, McNay JL. Effect of oral dose size on hydralazine kinetics and vasodepressor response. Clinical Pharmacology and Therapeutics 36: 595–600, 1984PubMedCrossRefGoogle Scholar
  122. Silber BM, Holford NHG, Riegelman S. Dose-dependent elimination of propranolol and its major metabolites in humans. Journal of Pharmaceutical Sciences 72: 725–732, 1983PubMedCrossRefGoogle Scholar
  123. Simons FER, Friesen FR, Simons KG. Theophylline toxicity in term infants. American Journal of Diseases of Children 134: 39–41, 1980PubMedGoogle Scholar
  124. Sinko PJ, Amidon GL. Characterization of the oral absorption of β-lactam antibiotics: 1. Determination of intrinsic membrane absorption parameters in the rat intestine in situ. Pharmaceutical Research 5: 645–650, 1988Google Scholar
  125. Sjövall J, Alvan G, Westerlund D. Oral cyclacilin interacts with the absorption of oral ampicillin, amoxicilin and bacampicilin. European Journal of Clinical Pharmacology 29: 495–502, 1985PubMedCrossRefGoogle Scholar
  126. Straka RJ, Lalonde RL, Pieper JA, Bottorff MB, Mirvis DM. Nonlinear pharmacokinetics of unbound propranolol after oral administration. Journal of Pharmaceutical Sciences 76: 521–524, 1987PubMedCrossRefGoogle Scholar
  127. Tang-Liu DDS, Tozer TN, Riegelman S. Dependence of renal clearance on urine flow: a mathematical model and its application. Journal of Pharmaceutical Sciences 72: 154–158, 1983PubMedCrossRefGoogle Scholar
  128. Tang-Liu DDS, Williams RL, Riegelman S. Nonlinear theophylline elimination. Clinical Pharmacology and Therapeutics 31: 358–369, 1982PubMedCrossRefGoogle Scholar
  129. Tozer TN, Tang-Liu DDS, Riegelman S. Linear vs. nonlinear kinetics. In Breimer & Speiser (Eds) Topics in pharmaceutical sciences, pp. 3–17, Elsevier, New York, 1981Google Scholar
  130. Tsuji A, Nakashima E, Kagami I, Yamana T. Intestinal absorption mechanism of amphoteric β-lactam antibiotics I: comparative absorption and evidence for saturable transport of amino-β-lactam antibiotics by in situ rat small intestine. Journal of Pharmaceutical Sciences 70: 768–772, 1981PubMedCrossRefGoogle Scholar
  131. van Ginneken CAM, Russel FGM. Saturable pharmacokinetics in the renal excretion of drugs. Clinical Pharmacokinetics 16: 38–54, 1989PubMedCrossRefGoogle Scholar
  132. VanWoert MH. Phenylalanine and tyrosine metabolism in Parkinson’s disease treated with levodopa. Clinical Pharmacology and Therapeutics 12: 368–375, 1971Google Scholar
  133. Vicuna N, Lalka D, Burrow SR, McLean AJ, duSouich P, et al. Dose-dependent pharmacokinetic behavior of lidocaine in the conscious dog. Research Communications in Chemical Pathology and Pharmacology 22: 485–491, 1978PubMedGoogle Scholar
  134. Vožeh S, Follath F. Nomographic estimation of time to reach steady-state serum concentrations during Phenytoin therapy. European Journal of Clinical Pharmacology 17: 33–35, 1980PubMedCrossRefGoogle Scholar
  135. Vžeh S, Muir KT, Sheiner LB, Follath F. Predicting individual Phenytoin dosage. Journal of Pharmacokinetics and Biopharmaceutics 9: 131–146, 1981Google Scholar
  136. Wagner JG. Time to reach steady-state and prediction of steadystate concentrations for drugs obeying Michaelis-Menton elimination kinetics. Journal of Pharmacokinetics and Biopharmaceutics 6: 209–295, 1978PubMedGoogle Scholar
  137. Wagner JG. Predictability of verapamil steady-state plasma levels from single-dose data explained. Clinical Pharmacology and Therapeutics 36: 1–4, 1984PubMedCrossRefGoogle Scholar
  138. Wagner JG. Propranolol: pooled Michaelis-Menten parameters and the effect of input rate on bioavailability. Clinical Pharmacology and Therapeutics 37: 481–487, 1985PubMedCrossRefGoogle Scholar
  139. Wagner JG, Antal EJ, Elvin AT, Gillespie WR, Pratt EA, et al. Theoretical decrease in systemic availability with decrease in input rate at steady-state for first-pass drugs. Biopharmaceutics and Drug Disposition 6: 341–343, 1985CrossRefGoogle Scholar
  140. Wagner JG, Gyves JW, Stetson CL, Walker-Andrews SC, Wollner IS, et al. Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients. Cancer Research 46: 1499–1506, 1986PubMedGoogle Scholar
  141. Wagner JG, Pocchini AP, Vasiliades J. Prediction of steady-state verapamil plasma concentrations in children and adults. Clinical Pharmacology and Therapeutics 32: 172–181, 1982PubMedCrossRefGoogle Scholar
  142. Wilkinson PK. Pharmacokinetics of ethanol: a review. Alcoholism — Clinical and Experimental Research 4: 6–21, 1980CrossRefGoogle Scholar
  143. Wilkinson PK, Sedman AJ, Sakman E, Earhart RH, Weidler DJ, et al. Blood ethanol concentrations during and following constant-rate intravenous infusion of alcohol. Clinical Pharmacology and Therapeutics 19: 213–223, 1976PubMedGoogle Scholar
  144. Wilkinson PK, Sedman AJ, Sakman E, Kay DR, Wagner JG. Pharmacokinetics of ethanol after oral administration in the fasting state. Journal of Pharmacokinetics and Biopharmaceutics 5: 207–224, 1977PubMedGoogle Scholar
  145. Winne D. Formal kinetics of water and solute absorption with regard to intestinal blood flow. Journal of Theoretical Biology 27: 1–18, 1970PubMedCrossRefGoogle Scholar
  146. Winne D, Remischovsky J. Intestinal blood flow and absorption of nondissociable substances. Journal of Pharmacy and Pharmacology 22: 640–641, 1970PubMedCrossRefGoogle Scholar
  147. Wood JH, Thakker KM. Michaelis-Menten absorption kinetics in drugs: examples and implications. European Journal of Clinical Pharmacology 23: 183–188, 1982PubMedCrossRefGoogle Scholar
  148. Yuen GJ, Bell RD, Ludden TM. Phenytoin cumulation profiles. Research Communications in Chemical Pathology and Pharmacology 42: 355–368, 1983PubMedGoogle Scholar
  149. Yung S, Mayersohn M, Robinson JB. Ascorbic acid absorption in man: influence of divided dose and food. Life Sciences 28: 2505–2511, 1981PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Thomas M. Ludden
    • 1
    • 2
  1. 1.The University of Texas at AustinAustinUSA
  2. 2.Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioUSA

Personalised recommendations