Kinetics of a carbamazepine-ethosuximide interaction

Warren, James W.; Benmaman, Joseph D.; Wannamaker, Braxton B.

doi:10.1038/clpt.1980.216

Cited by 35 publications

(18 citation statements)

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“…This can be explained by an inducing effect of carbamazepine on the conversion of primidone to phenobarbital rather than by an inhibitory effect on phenobarbital elimination. In fact, no change in phenobarbital clearance was reported in a study comparing 25 patients taking both phenobarbital and carbamazepine versus phenobarbital alone .l 147] Carbamazepine has been reported to increase the metabolic clearance and to decrease the plasma concentration of ethosuximide [148,149] and valproic acid, ' 150-154] both interactions being clinically significant. In the case of valproic acid, the specific metabolic pathways induced by carbamazepine include glucuronidation, 0) oxidation, and ((}-I oxidation.l 155 ] The formation clearance of the hepatotoxic metabolite 4-ene-valproic acid may also increase 2-fold during comedication with carbamazepine, [155] an observation which may explain the increased susceptibility of enzyme-induced patients to valpro ate hepatotoxicity.…”

Section: Phenytoin Phenobarbital (Phenobarbitone) Primidone Ethosmentioning

confidence: 95%

Clinically Significant Pharmacokinetic Drug Interactions with Carbamazepine

Spina

Pisani

Perucca

1996

Clinical Pharmacokinetics

298

149

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Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions.

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Section: Phenytoin Phenobarbital (Phenobarbitone) Primidone Ethosmentioning

confidence: 95%

Clinically Significant Pharmacokinetic Drug Interactions with Carbamazepine

Spina

Pisani

Perucca

1996

Clinical Pharmacokinetics

298

149

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“…However, few studies have examined this aspect in detail, but those that have all confirm the prediction of a significantly accelerated clearance in the presence of carbamazepine, phenobarbital, primidone or phenytoin. [171][172][173] Daily doses of ethosuximide should be at least 20 to 25% higher on these poly therapies with respect to monotherapy to yield the same plasma concentrations.…”

Section: Ethosuximide Interactionsmentioning

confidence: 99%

Pharmacokinetic Interactions Between Antiepileptic Drugs

Riva¹,

Albani²,

Contin³

et al. 1996

Clinical Pharmacokinetics

151

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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 mitochondrial beta-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.

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“…phenobarbitone and other metabolic inducers in rats [10][11][12], the influence of concurrent enzyme inducing anticonvulsants on ethosuximide disposition in man has volunteers given phenobarbitone (100 mg day−1 for 5 days per week for 2 weeks) was about 25% higher than that observed in six untreated controls, but the duration of barbiturate treatment may not have been References sufficient for the inducing effect to develop fully. In a similar study [14 ], administration of a very low dose of…”

Section: Introductionmentioning

confidence: 99%

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

Giaccone

Bartoli

Gatti

et al. 1996

Brit J Clinical Pharma

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1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2Compared with controls, epileptic patients showed markedly shorter ethosuximide half‐lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., P<0.001) and higher apparent oral clearance (CL/F) values (15.3±3.8 vs 9.2±1.9 ml kg−1 h−1, P<0.001). The apparent volume of distribution (V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1 l kg−1, P<0.05). 3These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.

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Kinetics of a carbamazepine-ethosuximide interaction

Cited by 35 publications

References 0 publications

Clinically Significant Pharmacokinetic Drug Interactions with Carbamazepine

Clinically Significant Pharmacokinetic Drug Interactions with Carbamazepine

Pharmacokinetic Interactions Between Antiepileptic Drugs

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

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