Elsevier

The Lancet Neurology

Volume 2, Issue 6, June 2003, Pages 347-356
The Lancet Neurology

Review
Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs

https://doi.org/10.1016/S1474-4422(03)00409-5Get rights and content

Summary

There are two types of interactions between drugs, pharmacokinetic and pharmacodynamic. For antiepileptic drugs (AEDs), pharmacokinetic interactions are the most notable type, but pharmacodynamic interactions involving reciprocal potentiation of pharmacological effects at the site of action are also important. By far the most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism. Among old generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone induce the activity of several enzymes involved in drug metabolism, leading to decreased plasma concentration and reduced pharmacological effect of drugs, which are substrates of the same enzymes (eg, tiagabine, valproic acid, lamotrigine, and topiramate). In contrast, the new AEDs gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other AEDs. Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid. Among AEDs, the least potential interaction is associated with gabapentin and levetiracetam.

Section snippets

Mechanisms of drug interaction

There are two basic types of drug interactions, pharmacokinetic and pharmacodynamic.2, 4 Pharmacokinetic interactions involve a change in the absorption, distribution, or elimination of the affected drug and account for most of the interactions reported to date because they are easily identifiable by a change in drug concentrations in the plasma. Pharmacodynamic interactions, although also important, are less well recognised and are commonly inferred to explain apparently drug-induced changes

Susceptibility to drug interactions

The probability of a drug interaction occurring and the associated clinical consequences are dependent on several factors (panel). Apart from the characteristics of the drugs, patient-related factors have an important role. For example, the effect of a metabolic interaction on a specific CYP isoenzyme can vary among patients in relation to genetic and environmental factors that determine the contribution of that isoenzyme to overall drug elimination. Age is another important source of

Interactions mediated by enzyme induction

Carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of various CYP isoenzymes (table 1) and they also induce UGT and epoxide hydrolases.2, 25, 38, 62, 63 As a result, these compounds stimulate the metabolism of other AEDs, most notably valproic acid,64, 65 tiagabine,66 ethosuximide,67 lamotrigine,68, 69, 70 topiramate,71 zonisamide,72 oxcarbazepine and its active monohydroxy-metabolite,73 felbamate,74 and many benzodiazepine drugs.75, 76 (table 2). The metabolism of

Prevention and management of adverse AED interactions

AED interactions can have substantial effects on clinical outcome (figure 1), and a therapeutic algorithm for management options in response to such interactions has been proposed (figure 2). A few simple rules can help to limit adverse consequences of AED interactions.2, 139 Multiple drug therapy should be used only when it is clearly indicated. Most patients with epilepsy can be best managed with an individualised dose of a single AED. Most interactions are metabolically based and can be

Search strategy and selection criteria

Data for this review were identified by searches of Medline and PubMed with the terms “antiepileptic drug interactions” combined with individual drug names and drug groups; references from relevant articles; and searches of the authors' files. Searches were undertaken between the period Sept 2, 2002 and Feb 11, 2003. Abstracts were included only when a complete published article was not available. Only papers published in English were reviewed. The purpose of the article was not to

References (144)

  • PatsalosPN et al.

    The importance of drug interactions in epilepsy therapy

    Epilepsia

    (2002)
  • PatsalosPN et al.

    Antiepileptic drugs: A review of clinically significant drug interactions

    Drug Safety

    (1993)
  • PatsalosPN

    Pharmacokinetic and pharmacodynamic interactions: Principles and interpretative pitfalls

    Epileptologia

    (1998)
  • BauerLA

    Interference of oral phenytoin absorption by continuous nasogastric feeding

    Neurology

    (1982)
  • HattonRC

    Dietery interaction with phenytoin

    Clin Pharm

    (1984)
  • WordenJP et al.

    Phenytoin and nasogastric feedings

    Neurology

    (1984)
  • LinJH et al.

    Role of P-glycoprotein in pharmacokinetics

    Clin Pharmacokinet

    (2003)
  • HoffmeyerS et al.

    Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo

    Proc Natl Acad Sci USA

    (2000)
  • FrickerG et al.

    Relevance of P-glycoprotein for the enteral absorption of cyclosporine A: in vitro-in vivo correlation

    Br J Pharmacol

    (1996)
  • LownKS et al.

    Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporin

    Clin Pharmacol Ther

    (1997)
  • Meerum TerwgotJM et al.

    Co-administration of oral cyclosporin A enables oral therapy with paclitaxel

    Clin Cancer Res

    (1999)
  • MalingreMM et al.

    Coadministration of cyclosporine strongly enhances the oral bioavailability of decetaxel

    J Clin Oncol

    (2001)
  • PotschkaH et al.

    P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain

    Neuroreport

    (2001)
  • RizziM et al.

    Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance

    J Neurosci

    (2002)
  • PotschkaH et al.

    Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain

    Neuroreport

    (2001)
  • SisodiyaSM

    Mechanisms of antiepileptic drug resistance

    Curr Opin Neurol

    (2003)
  • CoxDS et al.

    Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches

    J Pharmacol Exp Ther

    (2002)
  • WacherVJ et al.

    Overlapping substrate specificities and tissue distribution of cytochrome P4503A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy

    Mol Carcinog

    (1995)
  • SchuetzEG et al.

    Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulated these proteins in human carcinoma cells

    Mol Pharmacol

    (1996)
  • JetteL et al.

    Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues

    Am J Physiol

    (1996)
  • PeruccaE

    The clinical pharmacology and therapeutic use of the new antiepileptic drugs

    Fund Clin Pharmacol

    (2001)
  • RolanPE

    Plasma protein binding displacement interactions: Why are they still regarded as clinically important?

    Br J Clin Pharmacol

    (1994)
  • SansomLN et al.

    What is the true clinical significance of plasma protein binding displacement interactions?

    Drug Safety

    (1995)
  • BenetLZ et al.

    Changes in plasma protein binding have little clinical relevance

    Clin Pharmacol Ther

    (2002)
  • PatsalosPN

    Therapeutic drug monitoring in epilepsy: principles and concepts

    Epilepsy Monit

    (2001)
  • PatsalosPN

    Therapeutic drug monitoring in epilepsy: the established and the new antiepileptic drugs

    Epilepsy Monit

    (2002)
  • PeruccaE et al.

    Interaction between phenytoin and valproic acid: Plasma protein binding and metabolic effects

    Clin Pharmacol Ther

    (1980)
  • PatsalosPN et al.

    Effect of sodium valproate on plasma protein binding of diphenylhydantoin

    J Neurol Neurosurg Psychiat

    (1977)
  • TsanaclisLM et al.

    Effect of valproate on free plasma phenytoin concentrations

    Br J Clin Pharmacol

    (1984)
  • RivaR et al.

    Time-dependent interaction between phenytoin and valproic acid

    Neurology

    (1985)
  • PatsalosPN et al.

    Concentration-dependent displacement of tiagabine by valproic acid

    Epilepsia

    (2002)
  • AndersonGD

    A mechanistic approach to antiepileptic drug interactions

    Ann Pharmacother

    (1998)
  • Spina E, Perucca E, Levy RH. Predictability of metabolic antiepileptic drug interactions. In: Majkowski J, Bourgeois B,...
  • PeruccaE et al.

    A comparative study of the enzyme inducing properties of anticonvulsant drugs in epileptic patients

    Br J Clin Pharmacol

    (1984)
  • SuT et al.

    Differential xenobiotic induction of CYP2A5 in mouse liver, kidney, lung, and olfactory mucosa

    Drug Metab Dispos

    (1998)
  • PatsalosPN et al.

    Effect of the removal of antiepileptic drugs on antipyrine kinetics in patients taking polytherapy

    Br J Clin Pharmacol

    (1988)
  • RendicS et al.

    Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors

    Drug Metab Rev

    (1997)
  • GreenMD et al.

    Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides

    Drug Metab Disp

    (1995)
  • BonatePL et al.

    Drug interactions at the renal level. Implications for drug development

    Clin Pharmacokinet

    (1998)
  • PowellJR et al.

    Phenobarbital clearance, elimination with alkaline diuresis, and bioavailability in adults

    Clin Pharmacol Ther

    (1981)
  • Cited by (376)

    • Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients

      2022, Brain and Development
      Citation Excerpt :

      Third, CPHT may have been affected by concomitant antiepileptic drugs. In this study, concomitant antiepileptic drugs that could decrease CPHT were sodium valproate, phenobarbital, and carbamazepine [19]. In particular, the drug interaction between sodium valproate and phenytoin is that of plasma protein binding displacement, which decreases CPHT but does not change free phenytoin concentration [20,21].

    View all citing articles on Scopus
    View full text