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©2013 UpToDate ® Print Email Pharmacologic properties of antiepileptic drugs Metabolism and clearance Enzyme induction/inhibition Protein binding, percent* Half life in adults (hours) Carbamazepine >90 percent metabolized by CYP 3A4 and 2C8 (minor) to active (epoxide) and inactive metabolites Dose adjustment is needed in severe renal or hepatic insufficiency Potent and broad spectrum inducer of CYP and P-gp 75 25-65 (initial use, enzyme inducing naive patient) 8-22 (after several weeks due to auto induction) Ethosuximide ~80 percent metabolized by CYP 3A4 and non-CYP transformations to inactive metabolites None <5 40-60 Felbamate 60 percent metabolized by CYP 3A4 and 2E1 (minor); ~30 percent renally excreted as unchanged drug Dose adjustment is needed in renal insufficiency Induces CYP 3A4 (moderate) Inhibits CYP 2C19 (minor) 25 13-22 (prolonged in renal insufficiency) Gabapentin >95 percent renally excreted as unchanged drug (does not undergo metabolism) Dose adjustment is needed in renal insufficiency None <5 5-7 (prolonged in renal insufficiency; >130 hours in anuria) Lacosamide >40 percent renally excreted as unchanged drug; 30 percent metabolized by non-CYP transformations (including methylation) to inactive metabolite Dose adjustment is needed in renal insufficiency Inhibits 2C19 (minor) <15 13 Lamotrigine >90 percent metabolized by non-CYP transformations (including glucuronidation) to inactive metabolites Dose adjustment is needed in moderate to severe renal or hepatic insufficiency May induce its own metabolism by glucuronidation (minor) 55 12-62 Levetiracetam >65 renally excreted as unchanged drug; 24 percent metabolized by non-CYP transformation (including hydrolysis) to inactive metabolites Dose adjustment is needed in renal insufficiency None <10 6-8 Oxcarbazepine Prodrug. >90 percent metabolized by non-CYP transformations to pharmacologically active and inactive metabolites Dose adjustment is needed in severe renal insufficiency Induces CYP 3A4 (moderate to severe) and glucuronidation but does not induce its own metabolism 40 9 (active metabolite, prolonged in renal insufficiency) Perampanel >90 percent metabolized by CYP 3A4, 3A5 and non-CYP transformations to inactive metabolites Dose adjustment is needed in mild or moderate hepatic insufficiency Appears to induce metabolism of progestin- containing hormonal contraceptives 95 105 Phenobarbital

Induces CYP 3A4 (moderate to severe) and glucuronidation but does not induce its own metabolism 40 9 (active metabolite, prolonged in renal insufficiency) Perampanel >90 percent metabolized by CYP 3A4, 3A5 and non-CYP transformations to inactive metabolites Dose adjustment is needed in mild or moderate hepatic insufficiency Appears to induce metabolism of progestin- containing hormonal contraceptives 95 105 Phenobarbital 75 percent metabolized by CYP 2C19, 2C9 (minor) and 2E1 (minor) to inactive metabolites; 25 percent excreted renally as unchanged drug Dose adjustment is needed in severe renal or hepatic insufficiency Potent and broad spectrum inducer of CYP and glucuronidation 45 75-110 Phenytoin >90 percent metabolized by CYP 2C9, 2C19 and 3A4 (minor) and non-CYP transformations to inactive metabolites; clearance is dose dependent, saturable, and may be subject to genetic polymorphism Dose adjustment is needed in severe renal or hepatic insufficiency; monitoring of free (unbound) concentrations also suggested Potent and broad spectrum inducer of CYP and glucuronidation 90-95 9- >42 (dose dependent) Pregabalin >95 excreted renally as unchanged drug Dose adjustment is needed in renal insufficiency None <5 6 Primidone 75 percent metabolized by CYP 2C19, 2C9 (minor) and 2E1 (minor) to active intermediates; ~25 percent excreted renally as unchanged drug Dose adjustment is needed in moderate and severe renal or hepatic insufficiency; close monitoring of plasma levels suggested Potent and broad spectrum inducer of CYP 0-20 10-15 (parent) 29-100 (active metabolite) Rufinamide >90 percent metabolized by non-CYP transformations to inactive metabolites Induces CYP 3A4 (minor) Inhibits CYP 2E1 (minor) 35 6-10 Tiagabine >90 percent metabolized by CYP 3A4 and non-CYP transformations to inactive metabolites None 95 7-9 2-5 (with enzyme-inducing AEDs) Topiramate >65 percent excreted renally as unchanged drug; <30 percent metabolized by non-CYP transformations to inactive metabolites; extent of metabolism is increased ~50 percent in patients receiving enzyme inducing AEDs Dose adjustment is needed in moderate and severe renal or hepatic insufficiency Inhibits 2C19 (minor) Induces CYP 3A4 (minor) 9-17 12-24 Valproate >95 percent undergoes complex transformations including CYP 2C9, 2C19, 2A6, glucuronidation and non-CYP metabolism Dose adjustment is needed in hepatic insufficiency Moderate broad spectrum inhibitor including CYP 2A6, 2B6, 2C9, 2C19, 2E1 and glucuronidation

Dose adjustment is needed in moderate and severe renal or hepatic insufficiency Inhibits 2C19 (minor) Induces CYP 3A4 (minor) 9-17 12-24 Valproate >95 percent undergoes complex transformations including CYP 2C9, 2C19, 2A6, glucuronidation and non-CYP metabolism Dose adjustment is needed in hepatic insufficiency Moderate broad spectrum inhibitor including CYP 2A6, 2B6, 2C9, 2C19, 2E1 and glucuronidation Minor or moderate inducer of CYP 2A6 80-95 7-16 Vigabatrin >70 percent excreted renally as unchanged drug Dose adjustment is needed in renal insufficiency Induces CYP 2C9 0 5-13 (unrelated to duration of action) Zonisamide >70 percent metabolized by CYP 3A4, 2C19 (minor) and non-CYP transformations Dose adjustment and/or slower titration is needed in mild renal insufficiency or hepatic insufficiency; not recommended in patients with moderate or severe renal insufficiency None 40 63 AEDs: antiepileptic drugs; CYP: cytochrome P450; P-gp: membrane P-glycoprotein multidrug resistance transporter * Highly protein-bound AEDs exhibit altered pharmacokinetics, including greater therapeutic and toxic effects and drug interactions, when given in usual doses to patients with low serum albumin or protein binding affinity (eg, due to nephrotic syndrome or acidosis).  Dose alteration is needed and monitoring of unbound (free) AED serum concentrations is suggested. See UpToDate topic for additional information. Modified from: Bazil CW. Antiepileptic drugs in the 21st century. CNS Spectr 2001; 6:756. Lacerda G, Krummel T, Sabourdy C, et al. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology 2006; 67:S28.