The comparative enzyme‐inducing properties of antiepileptic drugs [proceedings]

Perucca, Emilio; Hedges, A; Makki, KA; Hebdige, S; Wadsworth, J; Richens, A.

doi:10.1111/j.1365-2125.1979.tb00959.x

Cited by 16 publications

(7 citation statements)

References 5 publications

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“…The induction of CBZ metabolism by drugs such as phenobarbitone and phenytoin has been demonstrated (Christiansen & Dam, 1975). In contrast, animal and human studies have demonstrated a lack of significant enzyme-inducing properties by sodium valproate (Jordan, Shillingford & Steed, 1976;Perucca et al, 1979). Our finding that sodium valproate in combination with CBZ will increase the concentration of epoxide metabolite relative to the concentration of CBZ is therefore not consistent with a theory of enzyme induction and deserves further investigation.…”

Section: Discussioncontrasting

confidence: 56%

Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11‐epoxide in epileptic patients.

MacKichan¹,

Duffner²,

Cohen³

1981

Brit J Clinical Pharma

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1 The relationships between saliva, free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-EP) were studied in 24 chronically medicated epileptic patients. Four patients were taking CBZ alone, while 20 were taking one or more additional anticonvulsant drugs. 2 The free fraction of CBZ in plasma ranged from 0.19 to 0.33 (mean, 0.24) while the saliva:plasma (S:P) concentration ratios ranged from 0.20 to 0.35 (mean, 0.27). The free fraction of CBZ-EP in plasma ranged from 0.16 to 0.50 (mean, 0.32), while the S:P ratios ranged from 0.14 to 0.70 (mean, 0.43). The plasma protein binding and S:P ratios of these compounds appeared to be independent of age, sampling time and concurrently administered anticonvulsant drugs. 3 Significant linear relationships between saliva and total plasma concentrations and between saliva and free plasma concentrations were observed for both compounds (P < 0.001). However, salivary concentrations of CBZ and CBZ-EP were significantly more reliable as predictors of their respective free plasma concentrations than of their respective total plasma concentrations (P < 0.01). 4 It is concluded that measurement of CBZ and CBZ-EP in the saliva of chronically medicated epileptic patients provides a more reliable estimate of the pharmacodynamically active, free concentrations of these compounds in plasma.

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Section: Discussioncontrasting

confidence: 56%

Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11‐epoxide in epileptic patients.

MacKichan¹,

Duffner²,

Cohen³

1981

Brit J Clinical Pharma

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“…Calculated kinetic As phenytoin is almost exclusively eliminated by biotransformation (Hvidberg & Dam, 1976) the increase of the phenytoin clearance in presence of valproic acid is most likely to be due to enhancement of its metabolism. It is extremely unlikely that enzyme-induction is responsible for the observed interaction because sodium valproate is virtually devoid of enzyme-inducing properties in man (Perucca, Hedges, Makki, Hebdige, Wadsworth & Richens, 1979). The fact that the phenytoin half-life was not shortened during treatment with sodium valproate provides further evidence against induction of phenytoin metabolism.…”

Section: Resultsmentioning

confidence: 99%

Modification of phenytoin clearance by valproic acid in normal subjects.

Frigo¹,

Lecchini²,

Gatti³

et al. 1979

Brit J Clinical Pharma

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1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/‐ 0.17 v 0.38 +/‐ 0.11 ml min‐1 kg‐1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.

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“…Phenytoin, carbamazepine, phenobarbitone and primidone, when administered in therapeutic doses to patients with epilepsy, are potent inducers of hepatic drug-metabolising enzymes (Perucca and Richens, 1981;Perucca et al, 1979;Sotaniemi et al, 1978). A number of clinically important drug interactions are considered to be mediated by this effect.…”

Section: Drugs Whose Metabolism May Be Stimulated By Anticonvulsantsmentioning

confidence: 98%

Pharmacokinetic Interactions with Antiepileptic Drugs

Perucca

1982

Clinical Pharmacokinetics

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A large number of pharmacokinetic interactions with antiepileptic drugs have been reported in recent years. Among the interactions affecting the disposition of anticonvulsants, the most important are probably those resulting in inhibition of the metabolism of phenytoin, phenobarbitone and carbamazepine. Drugs which have been shown to inhibit the metabolism of these anticonvulsants and to precipitate clinical signs of intoxication in epileptic patients include sulthiame, valproic acid, chloramphenicol, certain sulphonamides, phenylbutazone, isoniazid and propoxyphene. Interactions affecting the plasma protein binding of antiepileptic drugs are less likely to cause long-lasting alterations in response, but they are important because they change the relationship between serum drug concentrations and clinical effect. Anticonvulsant agents may induce important alterations in the pharmacokinetics of other drugs. Phenytoin and phenobarbitone may decrease the gastrointestinal absorption of frusemide and griseofulvin, respectively. Many of the drugs used in the treatment of the adult epilepsies, including phenytoin, phenobarbitone, primidone and carbamazepine, are potent inducers of the hepatic microsomal enzymes. This results in an increased rate of metabolism and decreased clinical efficacy of a number of drugs, including dicoumarol, steroid oral contraceptives, metyrapone, glucocorticoid agents, doxycycline, quinidine and vitamin D.

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The comparative enzyme‐inducing properties of antiepileptic drugs [proceedings]

Cited by 16 publications

References 5 publications

Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11‐epoxide in epileptic patients.

Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11‐epoxide in epileptic patients.

Modification of phenytoin clearance by valproic acid in normal subjects.

Pharmacokinetic Interactions with Antiepileptic Drugs

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