Skip to main content

Pharmacokinetic of Antiepileptic Drugs in Patients with Hepatic or Renal Impairment

Clinical Pharmacokinetics volume 53, pages 29–49 (2014)Cite this article

Abstract

Many factors influence choice of antiepileptic drugs (AEDs), including efficacy of the drug for the indication (epilepsy, neuropathic pain, affective disorder, migraine), tolerability, and toxicity. The first-generation AEDs and some newer AEDs are predominately eliminated by hepatic metabolism. Other recent AEDs are eliminated by renal excretion of unchanged drug or a combination of hepatic metabolism and renal excretion. The effect of renal and hepatic disease on the dosing will depend on the fraction of the AED eliminated by hepatic and/or renal excretion, the metabolic isozymes involved, as well as the extent of protein binding, if therapeutic drug monitoring is used. For drugs that are eliminated by renal excretion, methods of estimating creatinine clearance can be used to determine dose adjustments. For drugs eliminated by hepatic metabolism, there are no specific markers of liver function that can be used to provide guidance in dosage adjustments. Based on studies with probe drugs, the hepatic metabolic enzymes are differentially affected depending on the cause and severity of hepatic disease, which can aid in predicting dose adjustment when clinical data are not available. Several AEDs are also associated with laboratory markers of mild hepatic dysfunction and, rarely, more severe hepatic injury. In contrast, the risk of renal injury from AEDs is generally low. In general, co-morbid hepatic or renal diseases influence the decision for the selection of an AED. For some patients dosing changes to their existing AEDs may be appropriate. For others, a change to another AED may be a better option.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. French JA, Gazzola DM. Antiepileptic drug treatment: new drugs and new strategies. Continuum (Minneap Minn). 2013;19(3 Epilepsy):643–55.

  2. Frye RF, Zgheib NK, Matzke GR, et al. Liver disease selectively modulates cytochrome P450—mediated metabolism. Clin Pharmacol Ther. 2006;80(3):235–45.

    CAS  PubMed  Google Scholar 

  3. Brater DC. Drug dosing in patients with impaired renal function. Clin Pharmacol Ther. 2009;86(5):483–9.

    CAS  PubMed  Google Scholar 

  4. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71(3):115–21.

    CAS  PubMed  Google Scholar 

  5. Perucca E. Age-related changes in pharmacokinetics: predictability and assessment methods. Int Rev Neurobiol. 2007;81:183–99.

    CAS  PubMed  Google Scholar 

  6. Anderson GD, Lynn AM. Optimizing pediatric dosing: a developmental pharmacologic approach. Pharmacotherapy. 2009;29(6):680–90.

    CAS  PubMed  Google Scholar 

  7. Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109(1–2):1–11.

    CAS  PubMed  Google Scholar 

  8. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.

    CAS  PubMed  Google Scholar 

  9. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70.

    CAS  PubMed  Google Scholar 

  10. Imai E, Horio M, Nitta K, et al. Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan. Am J Kidney Dis. 2007;50(6):927–37.

    PubMed  Google Scholar 

  11. Ma YC, Zuo L, Zhang CL, et al. Comparison of 99mTc-DTPA renal dynamic imaging with modified MDRD equation for glomerular filtration rate estimation in Chinese patients in different stages of chronic kidney disease. Nephrol Dial Transplant. 2007;22(2):417–23.

    PubMed  Google Scholar 

  12. Miller WG. Reporting estimated GFR: a laboratory perspective. Am J Kidney Dis. 2008;52(4):645–8.

    PubMed  Google Scholar 

  13. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.

    PubMed Central  PubMed  Google Scholar 

  14. Stevens LA, Claybon MA, Schmid CH, et al. Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities. Kidney Int. 2011;79(5):555–62.

    PubMed  Google Scholar 

  15. Horio M, Imai E, Yasuda Y, et al. Modification of the CKD epidemiology collaboration (CKD-EPI) equation for Japanese: accuracy and use for population estimates. Am J Kidney Dis. 2010;56(1):32–8.

    PubMed  Google Scholar 

  16. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(11):1122–37.

    CAS  PubMed  Google Scholar 

  17. Park EJ, Wu K, Mi Z, et al. A systematic comparison of Cockcroft-Gault and Modification of Diet in Renal Disease equations for classification of kidney dysfunction and dosage adjustment. Ann Pharmacother. 2012;46(9):1174–87.

    PubMed  Google Scholar 

  18. Park EJ, Pai MP, Dong T, et al. The influence of body size descriptors on the estimation of kidney function in normal weight, overweight, obese, and morbidly obese adults. Ann Pharmacother. 2012;46(3):317–28.

    PubMed  Google Scholar 

  19. Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol. 2009;65(8):757–73.

    CAS  PubMed  Google Scholar 

  20. Morgan DJ, Smallwood RA. Clinical significance of pharmacokinetic models of hepatic elimination. Clin Pharmacokinet. 1990;18(1):61–76.

    CAS  PubMed  Google Scholar 

  21. Williams RL, Schary WL, Blaschke TF, et al. Influence of acute viral hepatitis on disposition and pharmacologic effect of warfarin. Clin Pharmacol Ther. 1976;20(1):90–7.

    CAS  PubMed  Google Scholar 

  22. Williams RL, Blaschke TF, Meffin PJ, et al. Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide. Clin Pharmacol Ther. 1977;21(3):301–9.

    CAS  PubMed  Google Scholar 

  23. Kraus JW, Desmond PV, Marshall JP, et al. Effect of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther. 1978;24:411–9.

    CAS  PubMed  Google Scholar 

  24. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.

    CAS  PubMed  Google Scholar 

  25. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver and portal hypertension. Philadelphia: WB Saunders; 1964. p. 1–85.

    Google Scholar 

  26. Johnson TN, Boussery K, Rowland-Yeo K, et al. A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet. 2010;49(3):189–206.

    CAS  PubMed  Google Scholar 

  27. Ohnishi A, Murakami S, Akizuki S, et al. In vivo metabolic activity of CYP2C19 and CYP3A in relation to CYP2C19 genetic polymorphism in chronic liver disease. J Clin Pharmacol. 2005;45(11):1221–9.

    CAS  PubMed  Google Scholar 

  28. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol. 2003;9(2):359–63.

    CAS  PubMed  Google Scholar 

  29. Guengerich FP, Turvy CG. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J Pharmacol Exp Ther. 1991;256(3):1189–94.

    CAS  PubMed  Google Scholar 

  30. George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology. 1995;21(1):120–8.

    CAS  PubMed  Google Scholar 

  31. Zimmerer J, Tittor W, Degen P. Anti-rheumatic therapy in patients with liver diseases. Plasma levels of diclofenac and elimination of diclofenac and metabolites in urine of patients with liver disease [in German]. Fortschr Med. 1982;100(36):1683–8.

    CAS  PubMed  Google Scholar 

  32. Juhl RP, Van Thiel DH, Dittert LW, et al. Ibuprofen and sulindac kinetics in alcoholic liver disease. Clin Pharmacol Ther. 1983;34(1):104–9.

    CAS  PubMed  Google Scholar 

  33. Pacifici GM, Viani A, Franchi M, et al. Conjugation pathways in liver disease. Br J Clin Pharmacol. 1990;30(3):427–35.

    CAS  PubMed  Google Scholar 

  34. Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology. 1991;13(4):786–95.

  35. Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia. 1999;40(11):1471–83.

    CAS  PubMed  Google Scholar 

  36. McLean MJ. Clinical pharmacokinetics of gabapentin. Neurology. 1994;44(6 Suppl 5):S17–22 (discussion S31–2).

    Google Scholar 

  37. Urban TJ, Brown C, Castro RA, et al. Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin. Clin Pharmacol Ther. 2008;83(3):416–21.

    CAS  PubMed  Google Scholar 

  38. Blum RA, Comstock TJ, Sica DA, et al. Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther. 1994;56:154–9.

    CAS  PubMed  Google Scholar 

  39. Neurontin®: product information. New York: Parke Davis; 2010.

  40. Wong MO, Eldon MA, Keane WF, et al. Disposition of gabapentin in anuric subjects on hemodialysis. J Clin Pharmacol. 1995;35(6):622–6.

    CAS  PubMed  Google Scholar 

  41. Lal R, Sukbuntherng J, Luo W, et al. Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin Ther. 2012;34(1):201–13.

    CAS  PubMed  Google Scholar 

  42. Delahoy P, Thompson S, Marschner IC. Pregabalin versus gabapentin in partial epilepsy: a meta-analysis of dose-response relationships. BMC Neurol. 2010;10:104. doi:10.1186/471-2377-10-104.

    PubMed Central  PubMed  Google Scholar 

  43. Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol. 2010;50(8):941–50.

    CAS  PubMed  Google Scholar 

  44. Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43(3):277–83.

    CAS  PubMed  Google Scholar 

  45. Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia. 1999;40:1471–83.

    CAS  PubMed  Google Scholar 

  46. Willmore LJ, Abelson MB, Ben-Menachem E, et al. Vigabatrin: 2008 update. Epilepsia. 2009;50(2):163–73.

    CAS  PubMed  Google Scholar 

  47. Rey G, Pons G, Olive G. Vigabatrin. Clin Pharmacokinet. 1992;23:267–78.

    CAS  PubMed  Google Scholar 

  48. Haegele KD, Huebert ND, Ebel M, et al. Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Ther. 1988;44:558–65.

    CAS  PubMed  Google Scholar 

  49. SABRIL™: product information. Deerfield: Lundbeck, Inc.; 2009.

  50. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine: role of CYP3A4 and CYP2A8 in 10, 11 epoxide formation. Biochem Pharmacol. 1994;47:1969–79.

    CAS  PubMed  Google Scholar 

  51. Faigle JW, Feldmann KF. Carbamazepine: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrun BS, editors. Antiepileptic drugs. 5th ed. New York: Raven Press; 2002. p. 499–514.

    Google Scholar 

  52. Kandrotas RJ, Oles KS, Gal P, et al. Carbamazepine clearance in hemodialysis and hemoperfusion. DICP. 1989;23(2):137–40.

    CAS  PubMed  Google Scholar 

  53. Lazar JG, Rosenberg HC, Tietz E. Benzodiazepines. In: Wyllie E, editor. Treatment of epilepsy. 5th ed. Philadelphia: Lippincott, Williams & Wilkins; 2011. p. 668–89.

  54. Giraud C, Tran A, Rey E, et al. In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos. 2004;32(11):1279–86.

    CAS  PubMed  Google Scholar 

  55. Kosaki K, Tamura K, Sato R, et al. A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam. Brain Dev. 2004;26(8):530–4.

    PubMed  Google Scholar 

  56. Haigh JR, Pullar T, Gent JP, et al. N-desmethylclobazam: a possible alternative to clobazam in the treatment of refractory epilepsy? Br J Clin Pharmacol. 1987;23(2):213–8.

    CAS  PubMed  Google Scholar 

  57. Anderson G, Miller J. Benzodiazepines: chemistry, biotransformation and pharmacokinetics. In: Levy R, Mattson R, Meldrum B, Perrucca E, editors. Antiepileptic drugs. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 187–205.

    Google Scholar 

  58. Monjanel-Mouterde S, Antoni M, Bun H, et al. Pharmacokinetics of a single oral dose of clobazam in patients with liver disease. Pharmacol Toxicol. 1994;74:345–50.

    CAS  PubMed  Google Scholar 

  59. ONFI®: product information. Deerfield: Lundbeck Inc.; 2011.

  60. de Leon J, Spina E, Diaz FJ. Clobazam therapeutic drug monitoring: a comprehensive review of the literature with proposals to improve future studies. Ther Drug Monit. 2013;35(1):30–47.

    PubMed  Google Scholar 

  61. Seree EJ, Pisano PJ, Placidi M, et al. Identification of the human and animal hepatic cytochrome P450 involved in clonazepam metabolism. Fundam Clin Pharmacol. 1993;7:69–75.

    CAS  PubMed  Google Scholar 

  62. Pacifici GM, Viani A, Rizzo G, et al. Plasma protein binding of clonazepam in hepatic and renal insufficiency and after hemodialysis. Ther Drug Monit. 1987;9:369–73.

    CAS  PubMed  Google Scholar 

  63. Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet. 1978;3:72–91.

    CAS  PubMed  Google Scholar 

  64. Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55:347–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Kangas L, Kanto J, Forsstrom J, et al. The protein binding of diazepam and N-demethyldiazepam in patients with poor renal function. Clin Nephrol. 1976;5:114–8.

    CAS  PubMed  Google Scholar 

  66. Greenblatt DJ, Harmatz JS, Shader RI. Factors influencing diazepam pharmacokinetics: age, sex, and liver disease. Int J Clin Pharmacol Biopharm. 1978;16(4):177–9.

    CAS  PubMed  Google Scholar 

  67. Andreasen PB, Hendel J, Greisen G, et al. Pharmacokinetics of diazepam in disordered liver function. Eur J Clin Pharmacol. 1976;10(2):115–20.

    CAS  PubMed  Google Scholar 

  68. Cohen AF, Land GS, Breimer DD, et al. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin Pharmacol Ther. 1987;42:535–41.

    CAS  PubMed  Google Scholar 

  69. Marcellin P, de Bony F, Garret C, et al. Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol. 2001;51(5):410–4.

    CAS  PubMed  Google Scholar 

  70. Posner J, Cohen AF, Land G, et al. The pharmacokinetics of lamotrigine (BW430C) in healthy subjects with unconjugated hyperbilirubinaemia. Br J Clin Pharmacol. 1989;28:117–20.

    CAS  PubMed  Google Scholar 

  71. Wootton R, Soul-Lawton J, Rolan PE, et al. Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers. Br J Clin Pharmacol. 1997;43:23–7.

    CAS  PubMed  Google Scholar 

  72. Fillastre JP, Taburet AM, Fialaire A, et al. Pharmacokinetics of lamotrigine in patients with renal impairment: influence of haemodialysis. Drugs Exp Clin Res. 1993;19(1):25–32.

    CAS  PubMed  Google Scholar 

  73. Chung JY, Cho JY, Yu KS, et al. Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clin Pharmacol Ther. 2005;77(6):486–94.

    CAS  PubMed  Google Scholar 

  74. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981;6(2):89–105.

    CAS  PubMed  Google Scholar 

  75. Herman RJ, Chaudhary A, Szakacs CB. Disposition of lorazepam in Gilbert’s syndrome: effects of fasting, feeding, and enterohepatic circulation. J Clin Pharmacol. 1994;34(10):978–84.

    CAS  PubMed  Google Scholar 

  76. Morrison G, Chiang ST, Koepke HH, et al. Effect of renal impairment and hemodialysis on lorazepam kinetics. Clin Pharmacol Ther. 1984;35:646–52.

    CAS  PubMed  Google Scholar 

  77. Anderson GD, Saneto RP. Current oral and non-oral routes of antiepileptic drug delivery. Adv Drug Deliv Rev. 2012;64(10):911–8.

    CAS  PubMed  Google Scholar 

  78. Trouvin JH, Farinotti R, Haberer JP, et al. Pharmacokinetics of midazolam in anaesthetized cirrhotic patients. Br J Anaesth. 1988;60(7):762–7.

    CAS  PubMed  Google Scholar 

  79. Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol. 1989;29(3):272–7.

    CAS  PubMed  Google Scholar 

  80. MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut. 1986;27(2):190–5.

    CAS  PubMed  Google Scholar 

  81. Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology. 2001;34(6):1103–8.

    CAS  PubMed  Google Scholar 

  82. McConn DJ 2nd, Lin YS, Mathisen TL, et al. Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis. Clin Pharmacol Ther. 2009;85(4):387–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Vinik HR, Reves JG, Greenblatt DJ, et al. The pharmacokinetics of midazolam in chronic renal failure patients. Anesthesiology. 1983;59:390–4.

    CAS  PubMed  Google Scholar 

  84. 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;24:1401–3.

    CAS  PubMed  Google Scholar 

  85. Blaschke TF, Meffin PJ, Melmon KL, et al. Influence of acute viral hepatitis on phenytoin kinetics and protein binding. Clin Pharmacol Ther. 1975;17(6):685–91.

    CAS  PubMed  Google Scholar 

  86. Kumar R, Chawla YK, Garg SK, et al. Pharmacokinetics of omeprazole in patients with liver cirrhosis and extrahepatic portal venous obstruction. Methods Find Exp Clin Pharmacol. 2003;25(8):625–30.

    CAS  PubMed  Google Scholar 

  87. Adedoyin A, Arns PA, Richards WO, et al. Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther. 1998;64(1):8–17.

    CAS  PubMed  Google Scholar 

  88. Pique JM, Feu F, de Prada G, et al. Pharmacokinetics of omeprazole given by continuous intravenous infusion to patients with varying degrees of hepatic dysfunction. Clin Pharmacokinet. 2002;41(12):999–1004.

    CAS  PubMed  Google Scholar 

  89. Friel PN, Ojemann GA, Rapport RL, et al. Human brain phenytoin: correlation with unbound and total serum concentrations. Epilepsy Res. 1989;3(1):82–5.

    CAS  PubMed  Google Scholar 

  90. Anderson GD, Pak C, Doane KW, et al. Revised Winter–Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia. Ann Pharmacother. 1997;31:279–84.

    CAS  PubMed  Google Scholar 

  91. Reidenberg MM, Odar-Cederlof I, von Bahr C, et al. Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function. N Engl J Med. 1971;285(5):264–7.

    CAS  PubMed  Google Scholar 

  92. Blum MR, Riegelman S, Becker CE. Altered protein binding of diphenylhydamtoin in uremic plasma. N Engl J Med. 1972;286(2):109.

    CAS  PubMed  Google Scholar 

  93. Letteri JM, Mellk H, Louis S, et al. Diphenylhydantoin metabolism in uremia. N Engl J Med. 1971;285(12):648–52.

    CAS  PubMed  Google Scholar 

  94. Mauro LS, Mauro VF, Bachmann KA, et al. Accuracy of two equations in determining normalized phenytoin concentrations. DICP. 1989;23(1):64–8.

    CAS  PubMed  Google Scholar 

  95. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology. 2008;70(21):1950–8.

    CAS  PubMed  Google Scholar 

  96. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Fifth Eilat Conference (EILAT V). Epilepsy Res. 2001;43:11–58.

    CAS  PubMed  Google Scholar 

  97. BANZEL™: product information. Woodcliff Lake: Eisai Co., Ltd; 2011.

  98. Chiron C. Stiripentol. Neurotherapeutics. 2007;4(1):123–5.

    CAS  PubMed  Google Scholar 

  99. Levy RH, Loiseau P, Guyot M, et al. Michaelis–Menten kinetics of stiripentol in normal humans. Epilepsia. 1984;25:486–91.

    CAS  PubMed  Google Scholar 

  100. Moreland TA, Astoin J, Lepage F, et al. The metabolic fate of stiripentol in man. Drug Metab Dispos. 1986;14:654–62.

    CAS  PubMed  Google Scholar 

  101. Luer MS, Rhoney DH. Tiagabine: a novel antiepileptic drug. Ann Pharmacother. 1998;32:1173–80.

    CAS  PubMed  Google Scholar 

  102. Bopp BA, Gustavson L, Johnson MK, et al. Disposition and metabolism of orally administered 14C-Tiagabine in humans [abstract]. Epilepsia. 1992;33(Suppl 3):83.

    Google Scholar 

  103. Bopp BA, Nequist GD, Rodrigues AD. Role of the cytochrome P450 3A subfamily in the metabolism of [14C] tiagabine by human hepatic microsomes [abstract]. Epilepsia. 1995;36(Suppl 3):S158–9.

    Google Scholar 

  104. Thompson MS, Groes L, Schwietert H, et al. An open label sequence listed two period crossover pharmacokinetic trial evaluating the possible interaction between tiagabine and erythromycin during multiple administration to healthy volunteers [abstract]. Epilepsia. 1997;38(Suppl 3):64.

    Google Scholar 

  105. Lau AH, Gustavson LE, Sperelakis R, et al. Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function. Epilepsia. 1997;38:445–51.

    CAS  PubMed  Google Scholar 

  106. Cato A 3rd, Gustavson LE, Qian J, et al. Effect of renal impairment on the pharmacokinetics and tolerability of tiagabine. Epilepsia. 1998;39:43–7.

    CAS  PubMed  Google Scholar 

  107. Levy RH, Shen DD, Abbott FS, et al. Valproic acid: chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perrucca E, editors. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 780–800.

    Google Scholar 

  108. Cramer JA, Mattson RH, Bennett DM, et al. Variable free and total valproic acid concentrations in sole- and multidrug therapy. Ther Drug Monit. 1986;8:411–5.

    CAS  PubMed  Google Scholar 

  109. Klotz U, Rapp T, Muller WA. Disposition of valproic acid in patients with liver disease. Eur J Clin Pharmacol. 1978;13:55–60.

    CAS  PubMed  Google Scholar 

  110. Zimmerman CL, Patel IH, Levy RH, et al. Protein binding of valproic acid in the presence of elevated free fatty acids in patient and normal human serum. Epilepsia. 1981;22(1):11–7.

    CAS  PubMed  Google Scholar 

  111. Bruni J, Wang LH, Marbury TC, et al. Protein binding of valproic acid in uremic patients. Neurology. 1980;30(5):557–9.

    CAS  PubMed  Google Scholar 

  112. Fattore C, Perucca E. Novel medications for epilepsy. Drugs. 2011;71(16):2151–78.

    CAS  PubMed  Google Scholar 

  113. Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia. 2012;53(6):935–46.

    CAS  PubMed  Google Scholar 

  114. Almeida L, Potgieter JH, Maia J, et al. Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol. 2008;64(3):267–73.

    CAS  PubMed  Google Scholar 

  115. Maia J, Almeida L, Falcao A, et al. Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther. 2008;46(3):119–30.

    CAS  PubMed  Google Scholar 

  116. Bachmann K, He Y, Sarver JG, et al. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica. 2003;33(3):265–76.

    CAS  PubMed  Google Scholar 

  117. Buchanan RA, Kinkel AW, Smith TC. The absorption and excretion of ethosuximide. Int J Clin Pharmacol. 1973;7(2):213–8.

    CAS  PubMed  Google Scholar 

  118. Marbury TC, Lee CS, Perchalski RJ, et al. Hemodialysis clearance of ethosuximide in patients with chronic renal disease. Am J Hosp Pharm. 1981;38(11):1757–60.

    CAS  PubMed  Google Scholar 

  119. Palmer K, McTavish D. Felbamate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. Drugs. 1993;45:1041–65.

    CAS  PubMed  Google Scholar 

  120. FELBATOL™: product information. Somerset: MEDA Pharmaceuticals, Inc.; 2011.

  121. Glue P, Sulowicz W, Colucci R, et al. Single-dose pharmacokinetics of felbamate in patients with renal dysfunction. Br J Clin Pharmacol. 1997;44(1):91–3.

    CAS  PubMed  Google Scholar 

  122. Cawello W, Fuhr U, Hering U, et al. Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide. Clin Pharmacokinet. 2013;52(10):897–906.

    Google Scholar 

  123. Strolin Benedetti M, Whomsley R, Nicolas JM, et al. Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers. Eur J Clin Pharmacol. 2003;59(8–9):621–30.

    CAS  PubMed  Google Scholar 

  124. Brockmoller J, Thomsen T, Wittstock M, et al. Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests. Clin Pharmacol Ther. 2005;77(6):529–41.

    PubMed  Google Scholar 

  125. Keppra™: product information. Smyrna: UCB, Inc; 2009.

  126. French J. Use of levetiracetam in special populations. Epilepsia. 2001;42(Suppl 4):40–3.

    PubMed  Google Scholar 

  127. Theisohn M, Heimann G. Disposition of the antiepileptic drug oxcarbazepine and its metabolites in healthy volunteers. Eur J Clin Pharmacol. 1982;22:545–51.

    CAS  PubMed  Google Scholar 

  128. May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet. 2003;42(12):1023–42.

    CAS  PubMed  Google Scholar 

  129. Rouan MC, Lecaillon JB, Godbillon J, et al. The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites. Eur J Clin Pharmacol. 1994;47:161–7.

    CAS  PubMed  Google Scholar 

  130. Franco V, Crema F, Iudice A, et al. Novel treatment options for epilepsy: focus on perampanel. Pharmacol Res. 2013;70(1):35–40.

    CAS  PubMed  Google Scholar 

  131. Anderson GD. Phenobarbital: chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perrucca E, editors. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 496–503.

    Google Scholar 

  132. Hargraves JA, Howald WN, Racha JK, et al. Identification of enzymes responsible for the metabolism of phenobarbital [abstract]. Int Soc Stud Xenobiotics Proc. 1996;10:259.

    Google Scholar 

  133. Alvin J, McHorse T, Hoyumpa A, et al. The effect of liver disease in man on the disposition of phenobarbital. J Pharmacol Exp Ther. 1975;192:224–35.

    CAS  PubMed  Google Scholar 

  134. Tompson DJ, Crean CS. Clinical pharmacokinetics of retigabine/ezogabine. Curr Clin Pharmacol. Epub 2013 Jan 15.

  135. Hempel R, Schupke H, McNeilly PJ, et al. Metabolism of retigabine (D-23129), a novel anticonvulsant. Drug Metabol Dispos. 1999;27(5):613–22.

    CAS  Google Scholar 

  136. Hermann R, Borlak J, Munzel U, et al. The role of Gilbert’s syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine. Pharmacogenomics J. 2006;6(3):211–9.

    CAS  PubMed  Google Scholar 

  137. POTIGA®: product information. Research Triangle Park: GlaxoSmithKline; 2013.

  138. Doose DR, Walker SA, Gisclon LG, et al. Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug. J Clin Pharmacol. 1996;36(10):884–91.

    CAS  PubMed  Google Scholar 

  139. Britzi M, Soback S, Isoherranen N, et al. Analysis of topiramate and its metabolites in plasma and urine of healthy subjects and patients with epilepsy by use of a novel liquid chromatography-mass spectrometry assay. Ther Drug Monit. 2003;25(3):314–22.

    CAS  PubMed  Google Scholar 

  140. TOPAMAX™: product information. Titusville: Janssen Pharmaceuticals, Inc.; 2011.

  141. Doose DR, Streeter AJ. Topiramate: chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perrucca E, editors. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 727–34.

    Google Scholar 

  142. Gisclon LG, Curtin CR. The pharmacokinetics of topiramate in subjects with end-stage renal disease undergoing hemodialysis [abstract]. Clin Pharmacol Ther. 1994;55(2):196.

    Google Scholar 

  143. Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia. 2007;48(3):435–41.

    CAS  PubMed  Google Scholar 

  144. Zonegran®: product information. San Francisco: Elan Pharmaceuticals; 2002.

  145. Schentag JJ, Gengo FM, Wilton JH, et al. Influence of phenobarbital, cimetidine, and renal disease on zonisamide kinetics [abstract]. Pharm Res. 1987;4(Suppl. 4):S79.

    Google Scholar 

  146. Bryantt AE, Dreifuss FE. Hepatotoxicity associated with antiepileptic drug therapy. CNS Drugs. 1995;4(2):99–113.

    Google Scholar 

  147. Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia. 2007;48(7):1223–44.

    CAS  PubMed  Google Scholar 

  148. Handoko KB, van Puijenbroek EP, Bijl AH, et al. Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring. Drug Saf. 2008;31(8):695–702.

    CAS  PubMed  Google Scholar 

  149. Hirsch LJ, Arif H, Nahm EA, et al. Cross-sensitivity of skin rashes with antiepileptic drug use. Neurology. 2008;71(19):1527–34.

    CAS  PubMed  Google Scholar 

  150. Bryant AE 3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology. 1996;46(2):465–9.

    PubMed  Google Scholar 

  151. Appleton RE, Farrell K, Applegarth DA, et al. The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects. Can J Neurol Sci. 1990;17(2):145–8.

    CAS  PubMed  Google Scholar 

  152. Krahenbuhl S, Brandner S, Kleinle S, et al. Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. Liver. 2000;20(4):346–8.

    CAS  PubMed  Google Scholar 

  153. Koenig SA, Buesing D, Longin E, et al. Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003. Epilepsia. 2006;47(12):2027–31.

    CAS  PubMed  Google Scholar 

  154. Dickinson RG, Bassett ML, Searle J, et al. Valproate hepatotoxicity: a review and report of two instances in adults. Clin Exp Neurol. 1985;21:79–91.

    CAS  PubMed  Google Scholar 

  155. Yamamoto Y, Takahashi Y, Imai K, et al. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia. 2013;54(6):983–9.

    CAS  PubMed  Google Scholar 

  156. Yamamoto Y, Takahashi Y, Suzuki E, et al. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res. 2012;101(3):202–9.

    CAS  PubMed  Google Scholar 

  157. Knights MJ, Finlay E. The effects of sodium valproate on the renal function of children with epilepsy. Pediatr Nephrol. Epub 2013 May 30.

  158. Unay B, Akin R, Sarici SU, et al. Evaluation of renal tubular function in children taking anti-epileptic treatment. Nephrology. 2006;11(6):485–8.

    CAS  PubMed  Google Scholar 

  159. Verrotti A, Greco R, Pascarella R, et al. Renal tubular function in patients receiving anticonvulsant therapy: a long-term study. Epilepsia. 2000;41(11):1432–5.

    CAS  PubMed  Google Scholar 

  160. Lamb EJ, Stevens PE, Nashef L. Topiramate increases biochemical risk of nephrolithiasis. Ann Clin Biochem. 2004;41(Pt 2):166–9.

    PubMed  Google Scholar 

  161. Mahmoud AA, Rizk T, El-Bakri NK, et al. Incidence of kidney stones with topiramate treatment in pediatric patients. Epilepsia. 2011;52(10):1890–3.

    CAS  PubMed  Google Scholar 

  162. Kubota M, Nishi-Nagase M, Sakakihara Y, et al. Zonisamide—induced urinary lithiasis in patients with intractable epilepsy. Brain Dev. 2000;22(4):230–3.

    CAS  PubMed  Google Scholar 

  163. Miyamoto A, Sugai R, Okamoto T, et al. Urine stone formation during treatment with zonisamide. Brain Dev. 2000;22(7):460.

    CAS  Google Scholar 

  164. Lockwood AH, Yap EW, Wong WH. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metabol. 1991;11(2):337–41.

    CAS  Google Scholar 

  165. Sotaniemi EA, Rautio A, Backstrom M, et al. CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients. Br J Clin Pharmacol. 1995;39(1):71–6.

    CAS  PubMed  Google Scholar 

  166. Chalon SA, Desager JP, Desante KA, et al. Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites. Clin Pharmacol Ther. 2003;73(3):178–91.

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Pharmacy and Regional Epilepsy Center, University of Washington, Box 357630, Seattle, WA, 98195, USA

    Gail D. Anderson

  2. Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, 98195, USA

    Shahin Hakimian

Authors
  1. Gail D. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shahin Hakimian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gail D. Anderson.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 29 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Anderson, G.D., Hakimian, S. Pharmacokinetic of Antiepileptic Drugs in Patients with Hepatic or Renal Impairment. Clin Pharmacokinet 53, 29–49 (2014). https://doi.org/10.1007/s40262-013-0107-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-013-0107-0

Keywords

  • Pregabalin
  • Zonisamide
  • Lacosamide
  • Tiagabine
  • Felbamate