| Metabolism and clearance | Enzyme or transporter induction/inhibition* | Protein binding (%)¶ | Half-life in adults (hours) | |
| Brivaracetam | Metabolized primarily by CYP-independent hydrolysis (60%) and CYP2C19 (30%) Dose adjustment is needed in hepatic impairment | Inhibits epoxide hydroxylaseΔ | ≤20 | 9 |
| Cannabidiol | Hepatic (primarily) and gut by CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7 to active metabolite 7-OH-CBD and then to inactive metabolite 7-COOH-CBD Dose adjustment is needed in moderate to severe hepatic impairment | Inhibits BCRP/ABCG2, BSEP/ABCB11, CYP2C19 (moderate) May increase serum concentration of clobazam and the active metabolite(s) of clobazam | >94 | 56 to 61 |
| Carbamazepine | >90% metabolized by CYPs 3A4 (major) and 1A2/2C8 (minor) to active (epoxide) and inactive metabolites Dose adjustment is needed in severe renal impairment; use is not recommended in moderate or severe hepatic impairment | Potent and broad-spectrum inducer of CYP, UGT-glucuronidation, and P-gp | 75 | 25 to 65 (initial use, enzyme-inducing naive patient) 8 to 22 (after several weeks due to auto-induction) |
| Cenobamate | Primarily metabolized by glucuronidation via UGT2B7 and to a lesser extent by UGT2B4, and by oxidation via CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5 Dose adjustment is needed for hepatic impairment; not recommended for patients with severe hepatic impairment or end-stage renal disease | May increase serum concentrations of clobazam, phenobarbital, phenytoin, and CYP2C19 substrates May decrease serum concentrations of carbamazepine, lamotrigine, and CYP2B6 and CYP3A substrates | 60 | 50 to 60 hours |
| Clobazam | >90% metabolized by CYPs 3A4, 2C19, 2B6 and non-CYP transformations to active (N-desmethylclobazam) and inactive metabolites Active metabolite is primarily metabolized by CYP2C19 Dose adjustment is needed in hepatic impairment | Inhibits CYP2D6 (weak) | 80 to 90 (clobazam, parent drug) 70 (N-desmethylclobazam, active metabolite) | 36 to 42 (clobazam, parent drug) 71 to 82 (N-desmethylclobazam, active metabolite) |
| Eslicarbazepine | Prodrug; <33% of active form undergoes UGT-glucuronidation (including <5% metabolized to oxcarbazepine); 66% is excreted renally as unchanged drug Dose adjustment is needed for renal impairment; not recommended in patients with severe hepatic impairment | Induces CYP3A4 (moderate) Inhibits CYP2C19 (weak) | <40 | 13 to 20 (prolonged in renal insufficiency) |
| Ethosuximide | ~80% metabolized by CYP3A4 (major) and non-CYP transformations to inactive metabolites | None | <5 | 40 to 60 |
| Felbamate | 50% metabolized by CYPs 3A4, 2E1 (minor); ~50% renally excreted as unchanged drug Dose adjustment is needed in renal impairment | Increases conversion of carbamazepine to active epoxide metabolite; mechanism not established Inhibits CYP2C19 (weak) | 25 | 13 to 22 (prolonged in renal insufficiency) |
| Gabapentin | >95% renally excreted as unchanged drug (ie, does not undergo hepatic metabolism) Dose adjustment is needed in renal impairment | None | <5 | 5 to 7 (prolonged in renal insufficiency; >130 hours in anuria) |
| Lacosamide | 40% renally excreted as unchanged drug; 30% metabolized by non-CYP transformations (including methylation) to inactive metabolite Dose adjustment is needed in hepatic and renal impairment | None | <15 | 13 |
| Lamotrigine | >90% metabolized by UGT-glucuronidation and other non-CYP transformations to inactive metabolites Dose adjustment is needed in moderate to severe renal or hepatic impairment | May induce its own metabolism by UGT-glucuronidation (minor) | 55 | 12 to 62 |
| Levetiracetam | >65% renally excreted as unchanged drug; 24% metabolized by non-CYP transformation (including amidase hydrolysis) to inactive metabolites Dose adjustment is needed in renal impairment | None | <10 | 6 to 8 |
| Oxcarbazepine | Prodrug; 70% of active (MHD) form undergoes UGT-glucuronidation; 30% is renally excreted as unchanged active drug Dose adjustment is needed in severe renal impairment | Induces CYP3A4 (weak) and UGT-glucuronidation but does not induce its own metabolism | 40 | 9 (active metabolite, prolonged in renal insufficiency) |
| Perampanel | >70% metabolized by CYPs 3A4, 3A5 and non-CYP transformations to inactive metabolites Dose adjustment is needed in mild or moderate hepatic impairment | Appears to induce metabolism of progestin-containing hormonal contraceptives | 95 | 105 |
| Phenobarbital | 75% metabolized by CYPs 2C19, 2C9 (minor) and glucosidase hydrolysis and 2E1 (minor) to inactive metabolites; 25% excreted renally as unchanged drug Dose adjustment is needed in severe renal or hepatic impairment | Potent and broad-spectrum inducer of CYP and UGT-glucuronidation | 55 | 75 to 110 |
| Phenytoin | >90% metabolized by CYPs 2C9, 2C19, 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 UGT-glucuronidation | 90 to 95 | 9 to >42 (dose dependent) |
| Pregabalin | >95% excreted renally as unchanged drug Dose adjustment is needed in renal impairment | None | <5 | 6 |
| Primidone | 75% metabolized by CYPs 2C19, 2C9 (minor) and 2E1 (minor) to active intermediates; ~25% excreted renally as unchanged drug Dose adjustment is needed in moderate and severe renal or hepatic impairment; close monitoring of plasma levels suggested | Potent and broad-spectrum inducer of CYP | 0 to 20 | 10 to 15 (parent) 29 to 100 (active metabolite) |
| Rufinamide | >90% metabolized by non-CYP transformations (hydrolysis) to inactive metabolites | Induces CYP3A4 (weak) | 35 | 6 to 10 |
| Stiripentol | Metabolized primarily in the liver by CYP450 enzymes CYP2C19, CYP3A4, and glucuronidation | Inhibits CYP3A4, CYP2C19, P-gp, and BCRP | 99 | 4.5 to 13 |
| Tiagabine | >90% metabolized by CYP3A4 and non-CYP transformations to inactive metabolites | None | 95 | 7 to 9 2 to 5 (with enzyme-inducing antiseizure medications) |
| Topiramate | >65% excreted renally as unchanged drug; <30% metabolized by non-CYP transformations to inactive metabolites; extent of metabolism is increased ~50% in patients receiving enzyme-inducing antiseizure medications Dose adjustment is needed in moderate and severe renal or hepatic impairment | None | 9 to 17 | 12 to 24 |
| Valproate | >95% undergoes complex transformations including CYPs 2C9, 2C19, 2A6, UGT-glucuronidation and other non-CYP transformation Dose adjustment is needed in hepatic impairment | None | 80 to 95 | 7 to 16 |
| Vigabatrin | >90% excreted renally as unchanged drug Dose adjustment is needed in renal impairment | None | 0 | 5 to 13 (unrelated to duration of action) |
| Zonisamide | >65% metabolized by CYPs 3A4, 2C19 (minor) and non-CYP transformations Dose adjustment and/or slower titration is needed in mild renal impairment or hepatic impairment; not recommended in patients with moderate or severe renal impairment | None | 50 | 63 |
CYP: cytochrome P450; MHD: monohydroxy derivative active form of oxcarbazepine; P-gp: membrane P-glycoprotein multidrug resistance transporter; UGT-glucuronidation: metabolism by uridine 5'diphosphate-glucuronyltransferases.
* The inhibitors and inducers of CYP or UGT drug metabolism and P-gp transporters listed in this table can alter serum concentrations of drugs that are dependent upon these enzymes or transporters for elimination, activation, or bioavailability. Classifications are based on US Food and Drug Administration guidance [4, 5]. Other sources may use a different classification system resulting in some agents being classified differently. Specific interactions should be assessed using a drug interaction program such as Lexicomp interactions included within UpToDate.
¶ Highly protein-bound antiseizure medications 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) antiseizure medication serum concentrations is suggested. Refer to UpToDate topic for additional information.
Δ Inhibitors of epoxide hydroxylase (eg, brivaracetam) can decrease metabolism of phenytoin and active metabolite of carbamazepine; refer to UpToDate topic.Additional data from:
