Pharmacokinetic Interactions with Antiepileptic Drugs

Perucca, Emilio

doi:10.2165/00003088-198207010-00004

Cited by 83 publications

(37 citation statements)

References 224 publications

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“…Its metabolism is primarily via CYP2C9, although CYP3A4 and CYP1A2 also are involved (105). Enzyme-inducing AEDs, such as PB, PHT, and CBZ can reduce the anticoagulant effects of both drugs by increasing their metabolism, possibly via an induction of CYP2C9 (106,107). During polytherapy, care must be taken to maintain appropriate plasma concentrations of dicoumarol/warfarin, as significant changes in plasma concentration could be life-threatening; this is achieved by checking the patient's coagulation function.…”

Section: Dicoumarol and Warfarinmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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Section: Dicoumarol and Warfarinmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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“…Among the latter, carbamazepine, phenytoin, phenobarbitone and primidone are potent inducers of the hepatic microsomal drug metabolizing enzymes (Perucca et al, 1984) and cause by this mechanism a large number of clinically significant interactions (Perucca, 1982;Pisani et al, 1990), including a reduction in the oral availability of drugs which, like dihydropyridines, undergo substantial first-pass metabolism (Capewell etal., 1988;Perucca & Richens, 1979). Of the main drugs used in the long-term treatment of the major epilepsies, only valproic acid is devoid of enzyme-inducing properties (Perucca et al, 1984), but a risk of interaction still exists because of the capacity of this compound to act as an inhibitor of oxidative (Kapetanovic et al, 1981) and non-oxidative (Jawad et al, 1987) 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 and 36 h after drug administration.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of valproic acid and enzyme‐inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.

Tártara¹,

Galimberti²,

Manni³

et al. 1991

Brit J Clinical Pharma

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1. The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme‐inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2. Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven‐fold (P less than 0.01) in patients taking enzyme‐inducing anticonvulsants and increased by about 50% (P less than 0.05) in patients taking sodium valproate. 3. Nimodipine half‐lives were shorter in enzyme‐induced patients than in controls (3.9 +/‐ 2.0 h vs 9.1 +/‐ 3.4 h, means +/‐ s.d., P less than 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate‐treated patients, half‐lives (8.2 +/‐ 1.8 h) were similar to those found in controls.

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“…Urinary recovery of the metabolic product, hydroxyphenylphenylhydantoin (HPPH), and its glucuronide conjugate accounts for 60 to 90% of an oral dose (Glazko et al, 1982). Other drugs have been shown to reduce the clearance of phenytoin (Perucca, 1982). Because of the nonlinear kinetics, changes in clearance will produce disproportionate changes in plasma concentrations and, given the narrow therapeutic range of phenytoin, there is an increased likelihood of poor seizure control or toxicity.…”

Section: Introductionmentioning

confidence: 99%

Lack of effect of erythromycin on the pharmacokinetics of single oral doses of phenytoin.

Milne

Coulthard

Nation

et al. 1988

Brit J Clinical Pharma

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The effect of erythromycin on the pharmacokinetics of phenytoin was studied in eight healthy volunteers using a balanced randomised cross-over design. Volunteers received a single oral dose of 400 mg of phenytoin sodium during each phase. During the treatment phase, the phenytoin sodium dose was administered 4.5 days after the commencement of a 7 day course of erythromycin base (250 mg every 6 h). There was no significant difference between the control and treatment phases (P > 0.05) with respect to the area under the plasma phenytoin concentration-time curve, the fraction of phenytoin unbound in plasma, the area under the unbound phenytoin concentration-time curve, the elimination half-life of phenytoin or the fraction of the dose excreted in urine as free and conjugated hydroxyphenylphenylhydantoin. This single dose study indicated that the intrinsic clearance of unbound phenytoin was unaffected by the concurrent administration of erythromycin.

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Pharmacokinetic Interactions with Antiepileptic Drugs

Cited by 83 publications

References 224 publications

The Importance of Drug Interactions in Epilepsy Therapy

The Importance of Drug Interactions in Epilepsy Therapy

Differential effects of valproic acid and enzyme‐inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.

Lack of effect of erythromycin on the pharmacokinetics of single oral doses of phenytoin.

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