Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations

Roberto Riva, Fiorenzo Albani, Manuela Contin, Agostino Baruzzi

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochofidrial β-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

Original languageEnglish
Pages (from-to)470-493
Number of pages24
JournalClinical Pharmacokinetics
Volume31
Issue number6
Publication statusPublished - 1996

Fingerprint

Anticonvulsants
Pharmacokinetics
Valproic Acid
felbamate
Cytochrome P-450 Enzyme System
Pharmaceutical Preparations
Protein Isoforms
Enzymes
Phenobarbital
Ethosuximide
Vigabatrin
zonisamide
Carbamazepine
Phenytoin
Liver
Primidone
Epoxide Hydrolases
Glucuronosyltransferase
Uridine Diphosphate
Drug Interactions

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations. / Riva, Roberto; Albani, Fiorenzo; Contin, Manuela; Baruzzi, Agostino.

In: Clinical Pharmacokinetics, Vol. 31, No. 6, 1996, p. 470-493.

Research output: Contribution to journalArticle

@article{95a8956166be4df8bb913f1c2a1d5e1b,
title = "Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations",
abstract = "Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochofidrial β-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.",
author = "Roberto Riva and Fiorenzo Albani and Manuela Contin and Agostino Baruzzi",
year = "1996",
language = "English",
volume = "31",
pages = "470--493",
journal = "Clinical Pharmacokinetics",
issn = "0312-5963",
publisher = "Adis International Ltd",
number = "6",

}

TY - JOUR

T1 - Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations

AU - Riva, Roberto

AU - Albani, Fiorenzo

AU - Contin, Manuela

AU - Baruzzi, Agostino

PY - 1996

Y1 - 1996

N2 - Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochofidrial β-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

AB - Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochofidrial β-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

UR - http://www.scopus.com/inward/record.url?scp=0029841727&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029841727&partnerID=8YFLogxK

M3 - Article

C2 - 8968658

AN - SCOPUS:0029841727

VL - 31

SP - 470

EP - 493

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

SN - 0312-5963

IS - 6

ER -