Clinical Pharmacokinetics

, Volume 46, Issue 4, pp 307–318 | Cite as

Effect of Time, Injury, Age and Ethanol on Interpatient Variability in Valproic Acid Pharmacokinetics after Traumatic Brain Injury

  • Gail D. Anderson
  • Nancy R. Temkin
  • Asaad B. Awan
  • H. Richard Winn
Original Research Article



Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-α, interferon-γ, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CLu) is equal to intrinsic or metabolic clearance.


The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CLu. In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CLu.

Study Design

Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CLu was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures.


CL and CLu were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The magnitude of the induction of CL was increased with decreased albumin concentrations, in addition to the presence of ethanol on admission, increased severity of head injury, tube feeding and total parenteral nutrition (TPN). The magnitude of induction of CLu was increased by older age, presence of ethanol on admission, increased severity of head injury, tube feeding, TPN, and if the patient had a post-injury neurosurgical procedure. The time to normalisation of CLu was significantly longer in patients with head injury plus other injuries compared with those with head injury alone.


As has been reported with other drugs, TBI results in a significant increase in the metabolism of valproic acid. The patient factors identified in this study that resulted in an increase in the magnitude and time course of the induction of CLu (ethanol, older age, presence of a neurosurgical procedure, severity of TBI and presence of multiple non-TBI injuries) have all been reported to cause a shift to the anti-inflammatory mediators IL-4 and IL-10. This suggests that the increase in hepatic metabolism after TBI may be due to the increased presence of antiinflammatory mediators in contrast to the inhibition effect of the pro-inflammatory mediators in non-TBI inflammation and infection.


Traumatic Brain Injury Head Injury Valproic Acid Total Parenteral Nutrition Hepatic Metabolism 
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.



This work was supported in part by a National Institutes of Health grant (No. NS19643). The authors would like to thank Jason Baber for his help with the data analysis. The authors have no conflicts of interest that are directly relevant to the content of this study.


  1. 1.
    Boucher BA, Hanes SD. Pharmacokinetic alterations after severe head injury. Clin Pharmacokinet 1998; 35: 209–21PubMedCrossRefGoogle Scholar
  2. 2.
    Bauer L, Edwards W, Dellinger E, et al. Importance of unbound phenytoin serum levels in head trauma patients. J Trauma 1983; 23: 1058–60PubMedCrossRefGoogle Scholar
  3. 3.
    Boucher B, Rodman J, Jaresko G, et al. Phenytoin pharmacokinetics in critically ill trauma patients. Clin Pharmacol Ther 1988; 44: 675–83PubMedCrossRefGoogle Scholar
  4. 4.
    Griebel M, Kearns G, Fiser D, et al. Phenytoin protein binding in pediatric patients with acute traumatic injury. Crit Care Med 1990; 18: 385–91PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson GD, Gidal BE, Hendryx RJ, et al. Decreased plasma protein binding of valproate in patients with acute head trauma. Br J Clin Pharmacol 1994; 37: 559–62PubMedCrossRefGoogle Scholar
  6. 6.
    Bajpai M, Roskos LK, Shen DD, et al. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolites. Drug Metab Dispos 1996; 24: 1401–3PubMedGoogle Scholar
  7. 7.
    Boucher B, Kuhl D, Fabian T, et al. The effect of neurotrauma on hepatic drug clearance. Clin Pharmacol Ther 1991; 50: 487–97PubMedCrossRefGoogle Scholar
  8. 8.
    Engel G, Hofmann U, Heidemann H, et al. Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther 1996; 59: 613–23PubMedCrossRefGoogle Scholar
  9. 9.
    Morgan EH, Oates PS. Mechanisms and regulation of intestinal iron absorption. Blood Cells Mol Dis 2002; 29(3): 384–99PubMedCrossRefGoogle Scholar
  10. 10.
    Renton KW. Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther 2001; 92(2–3): 147–63PubMedCrossRefGoogle Scholar
  11. 11.
    Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol 2006; 46: 123–49PubMedCrossRefGoogle Scholar
  12. 12.
    Renton KW. Cytochrome P450 regulation and drug biotransformation during inflammation and infection. Curr Drug Metab 2004; 5(3): 235–43PubMedCrossRefGoogle Scholar
  13. 13.
    Harbrecht BG, Frye RF, Zenati MS, et al. Cytochrome P-450 activity is differentially altered in severely injured patients. Crit Care Med 2005; 33(3): 541–6PubMedCrossRefGoogle Scholar
  14. 14.
    Aihara N, Hall JJ, Pitts LH, et al. Altered immunoexpression of microglia and macrophages after mild head injury. J Neurotrauma 1995; 12(1): 53–63PubMedCrossRefGoogle Scholar
  15. 15.
    Ott L, McClain CJ, Gillespie M, et al. Cytokines and metabolic dysfunction after severe head injury. J Neurotrauma 1994; 11(5): 447–72PubMedCrossRefGoogle Scholar
  16. 16.
    Gosain A, Gamelli RL. A primer in cytokines. J Burn Care Rehabil 2005; 26(1): 7–12PubMedCrossRefGoogle Scholar
  17. 17.
    Morganti-Kossmann MC, Lenzlinger PM, Hans V, et al. Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol Psychiatry 1997; 2: 133–6CrossRefGoogle Scholar
  18. 18.
    McClain C, Cohen D, Phillips R, et al. Increased plasma and ventricular fluid interleukin-6 levels in patients with head injury. J Lab Clin Med 1991; 118: 225–31PubMedGoogle Scholar
  19. 19.
    Kalabalikis P, Papazoglou K, Gouriotis D, et al. Correlation between serum IL-6 and CRP levels and severity of head injury in children. Intensive Care Med 1999; 25(3): 288–92PubMedCrossRefGoogle Scholar
  20. 20.
    Kossmann T, Stahel PF, Lenzlinger PM, et al. Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab 1997; 17: 280–9PubMedCrossRefGoogle Scholar
  21. 21.
    Neidhardt R, Keel M, Steckholzer U, et al. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. J Trauma 1997; 42(5): 863–71PubMedCrossRefGoogle Scholar
  22. 22.
    DiPiro JT, Howdieshell TR, Goddard JK, et al. Association of interleukin-4 plasma levels with traumatic injury and clinical course. Arch Surg 1995; 130(11): 1159–63PubMedCrossRefGoogle Scholar
  23. 23.
    Schmidt OI, Heyde CE, Ertel W, et al. Closed head injury: an inflammatory disease? Brain Res Brain Res Rev 2005; 48(2): 388–99PubMedCrossRefGoogle Scholar
  24. 24.
    Holmin S, Hojeberg B. In situ detection of intracerebral cytokine expression after human brain contusion. Neurosci Lett 2004; 369(2): 108–14PubMedCrossRefGoogle Scholar
  25. 25.
    Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of post-traumatic seizures: a randomized trial. J Neurosurg 1999; 91: 593–600PubMedCrossRefGoogle Scholar
  26. 26.
    Levy RH, Shen DD, Abbott FS, et al. Valproic acid: chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2002: 780–800Google Scholar
  27. 27.
    Anderson G, Awan A, Adams C, et al. Increases in metabolism of valproate and excretion of 6b-hydroxycortisol in patients with traumatic brain injury. Br J Clin Pharmacol 1998; 45: 101–95PubMedCrossRefGoogle Scholar
  28. 28.
    Kovacs SJ, Martin DE, Everitt DE, et al. Urinary excretion of 6b-hydroxycortisol as an in vivo marker for CYP3A induction: applications and recommendations. Clin Pharmacol Ther 1998; 63: 617–22PubMedCrossRefGoogle Scholar
  29. 29.
    Lum S-K, Tennyson D, Lizer D, et al. Development and evaluation of an avidin-biotin-based nephelometric assay for valproic acid on the Beckman Array [abstract]. Clin Chem 1993; 39(6): 1244Google Scholar
  30. 30.
    Scheyer RD, Cramer JA, Toftness BR, et al. In vivo determination of valproate binding constants during sole and multi-drug therapy. Ther Drug Monit 1990; 12(2): 117–23PubMedCrossRefGoogle Scholar
  31. 31.
    Kodama Y, Koike Y, Kimoto H, et al. Binding parameters of valproic acid to serum protein in healthy adults at steady state. Ther Drug Monit 1992; 14(1): 55–60PubMedCrossRefGoogle Scholar
  32. 32.
    Kodama Y, Kuranari M, Tsutsumi K, et al. Prediction of unbound serum valproic acid concentration by using in vivo binding parameters. Ther Drug Monit 1992; 14(5): 349–53PubMedCrossRefGoogle Scholar
  33. 33.
    Franke G, Diletti E, Hoffmann C, et al. Relative bioavailability of different valproic acid formulations. Int J Clin Pharmacol Ther 1995; 33(12): 653–7PubMedGoogle Scholar
  34. 34.
    Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale. Lancet 1974; II: 81–4CrossRefGoogle Scholar
  35. 35.
    Baker SP, O’Neill B, Haddon W, et al. The Injury Severity Score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974; 14: 187–96PubMedCrossRefGoogle Scholar
  36. 36.
    Bowdle AT, Patel IH, Levy RH, et al. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28(4): 486–92PubMedCrossRefGoogle Scholar
  37. 37.
    Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71(3): 115–21PubMedCrossRefGoogle Scholar
  38. 38.
    Young CC, Prielipp RC. Benzodiazepines in the intensive care unit. Crit Care Clin 2001; 17(4): 843–62PubMedCrossRefGoogle Scholar
  39. 39.
    Wagner BK, O’Hara DA. Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet 1997; 33(6): 426–53PubMedCrossRefGoogle Scholar
  40. 40.
    Power BM, Forbes AM, van Heerden PV, et al. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 1998; 34(1): 25–56PubMedCrossRefGoogle Scholar
  41. 41.
    Crews FT, Bechara R, Brown LA, et al. Cytokines and alcohol. Alcohol Clin Exp Res 2006; 30(4): 720–30PubMedCrossRefGoogle Scholar
  42. 42.
    Deaciuc IV. Alcohol and cytokine networks. Alcohol 1997; 14: 421–30PubMedCrossRefGoogle Scholar
  43. 43.
    Kovacs EJ, Duffner LA, Plackett TP. Immunosuppression after injury in aged mice is associated with a Thl-Th2 shift, which can be restored by estrogen treatment. Mech Ageing Dev 2004; 125(2): 121–3PubMedCrossRefGoogle Scholar
  44. 44.
    Kovacs EJ, Plackett TP, Witte PL. Estrogen replacement, aging, and cell-mediated immunity after injury. J Leukoc Biol 2004; 76(1): 36–41PubMedCrossRefGoogle Scholar
  45. 45.
    Plackett TP, Boehmer ED, Faunce DE, et al. Aging and innate immune cells. J Leukoc Biol 2004; 76(2): 291–9PubMedCrossRefGoogle Scholar
  46. 46.
    Woiciechowsky C, Asadullah K, Nestler D, et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 1998; 4(7): 808–13PubMedCrossRefGoogle Scholar
  47. 47.
    Asadullah K, Woiciechowsky C, Docke WD, et al. Immunodepression following neurosurgical procedures. Crit Care Med 1995; 23(12): 1976–83PubMedCrossRefGoogle Scholar
  48. 48.
    McKindley D, Boucher B, Hess M, et al. Effect of acute phase response on phenytoin metabolism in neurotrauma patients. J Clin Pharmacol 1997; 37: 129–39PubMedGoogle Scholar
  49. 49.
    Zheng YJ, Tam YK, Coutts RT. Endotoxin and cytokine released during parenteral nutrition. JPEN J Parenter Enteral Nutr 2004; 28(3): 163–8PubMedCrossRefGoogle Scholar
  50. 50.
    Earl-Salotti GI, Charland SL. The effect of parenteral nutrition on hepatic cytochrome P-450. JPEN J Parenter Enteral Nutr 1994; 18(5): 458–65PubMedCrossRefGoogle Scholar
  51. 51.
    Zaman N, Tam YK, Jewell LD, et al. Effects of intravenous lipid as a source of energy in parenteral nutrition associated hepatic dysfunction and lidocaine elimination: a study using isolated rat liver perfusion. Biopharm Drug Dispos 1997; 18(9): 803–19PubMedCrossRefGoogle Scholar
  52. 52.
    Ke J, Tam YK, Koo WW, et al. Effects of parenteral nutrition on hepatic elimination of lidocaine: a study using the isolated perfused rat liver. J Pharmacol Exp Ther 1990; 255(1): 351–6PubMedGoogle Scholar
  53. 53.
    Kappas A, Anderson KE, Conney AH, et al. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clin Pharmacol Ther 1976; 20: 643–53PubMedGoogle Scholar
  54. 54.
    Fagan TC, Walle T, Oexmann MJ, et al. Increased clearance of propranolol and theophylline by high-protein compared with high-carbohydrate diet. Clin Pharmacol Ther 1987; 41(4): 402–6PubMedCrossRefGoogle Scholar
  55. 55.
    Shiozaki T, Hayakata T, Tasaki O, et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury. Shock 2005; 23(5): 406–10PubMedCrossRefGoogle Scholar
  56. 56.
    Seekamp A, van Griensven M, Lehmann U, et al. Serum IL-6, IL-8 and IL-10 levels in multiple trauma compared to traumatic brain injury and combined trauma. Eur J Trauma 2002; 28: 83–9CrossRefGoogle Scholar
  57. 57.
    Kao CH, ChangLai SP, Chieng PU, et al. Gastric emptying in male neurologic trauma. J Nucl Med 1998; 39(10): 1798–801PubMedGoogle Scholar
  58. 58.
    Ott L, Young B, Phillips R, et al. Altered gastric emptying in the head-injured patient: relationship to feeding intolerance. J Neurosurg 1991; 74(5): 738–42PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2007

Authors and Affiliations

  • Gail D. Anderson
    • 1
  • Nancy R. Temkin
    • 2
  • Asaad B. Awan
    • 3
  • H. Richard Winn
    • 4
  1. 1.Departments of Pharmacy and Neurological Surgery, Schools of Pharmacy and MedicineUniversity of WashingtonSeattleUSA
  2. 2.Departments of Neurological Surgery and Biostatistics, Schools of Medicine and Public HealthUniversity of WashingtonSeattleUSA
  3. 3.Harborview Medical CenterSeattleUSA
  4. 4.Departments of Neurosurgery and NeuroscienceMount Sinai Medical SchoolNew YorkUSA

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