Valproic acid and plasma levels of phenytoin

Bruni, J.; Wilder, B. J.; Willmore, L. James; Barbour, Benjamin H.

doi:10.1212/wnl.29.6.904

Cited by 29 publications

(12 citation statements)

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“…More recently valproic acid has been shown to inhibit the metabolism of phenobarbitone, phenytoin and possibly ethosuximide (Wilder et al, 1978;Bruni et al, 1980;Perucca et al, 1980;Mattson & Cramer, 1980) and this would further support the possibility of an inhibitory effect on diazepam metabolism.…”

Section: Discussionmentioning

confidence: 95%

Valproic acid and diazepam interaction in vivo.

Dhillon¹,

Richens²

1982

Brit J Clinical Pharma

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I The effect of oral administration of sodium valproate (1500 mg daily) on the distribution and elimination kinetics of intravenously administered diazepam in six healthy volunteers has been studied. 2 During valproate administration the unbound fraction of diazepam in serum increased approximately two fold. This was accompanied by a significant increase in apparent volume of distribution and plasma clearance of diazepam. 3 There was a positive correlation between the change in free fraction and the increase in both apparent volume of distribution and plasma clearance of the drug. 4 The concentration of unbound diazepam in serum (calculated from the percent free diazepam and total serum concentration) was significantly higher during valproate administration. Both the intrinsic clearance and volume of distribution of unbound drug were significantly reduced. 5 Mean serum N-desmethyldiazepam levels were significantly lower during valproate coadministration. 6 These results suggest that valproic acid displaces diazepam from plasma protein binding sites and inhibits its metabolism.

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Section: Discussionmentioning

confidence: 95%

Valproic acid and diazepam interaction in vivo.

Dhillon¹,

Richens²

1982

Brit J Clinical Pharma

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“…Saturable plasma protein binding is evident at clinically relevant concentrations (Bowdle et al, 1980;Marty etal., 1982), while VPA elimination proceeds via pathways of glucuronidation and fatty acid oxidation (Schobben, 1983). Pharmacokinetic interactions occur with older anticonvulsant drugs, for example, displacement of phenytoin from its binding sites on circulating albumin (Monks et al, 1978;Cramer & Mattson, 1979;Levy & Koch, 1982) and inhibition of the metabolism of phenytoin (Bruni et al, 1979;Perucca et al, 1980), phenobarbitone (Kapetanovic et al, 1981) and ethosuximide (Mattson & Cramer, 1980;Pisani et al, 1984a).…”

Section: Introductionmentioning

confidence: 99%

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

Macphee

Mitchell

Wiseman

et al. 1988

Brit J Clinical Pharma

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1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design.2 VPA alone had no effect on antipyrine clearance, urinary 6p-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 ± 6 mg 1-1) well within the target range (50-100 mg I-1) for the drug.3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P < 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P < 0.02) and half-life of unbound CBZ 16% longer (P < 0.02) during VPA treatment. CBZ-10, 11 epoxide (CBZ-E) levels (52%) and CBZ-E/ CBZ ratios (45%) were both elevated by concurrent VPA (P < 0.05) and free CBZ fraction was increased by 7% (P < 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P < 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P < 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide. The effect of VPA on the psychomotor profile of a large single dose of CBZ was minimal. 6 Further studies in epileptic patients receiving both these anticonvulsant drugs are warranted to appraise the extent and clinical relevance of their interaction.

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“…When VPA was started in patients on a maintenance phenytoin regimen, it initially displaced phenytoin from protein-binding sites, resulting in a transient decrease in the total plasma phenytoin concentration (Bourgeois 1988). Because of inhibition of the metabolism of phenytoin, however, total phenytoin levels gradually increased and had returned to the pre-VPA level after 16 to 20 weeks (Bruni et al 1979). Since our patients had already been treated with the combination of VPA (in a standard tablet) and phenytoin for more than 3 months (mostly 6 months-5 years) before the change in VPA formulation, enzyme inhibition was considered not to be a likely cause of the rise in total plasma phenytoin level after the VPA formulation switch.…”

Section: Resultsmentioning

confidence: 99%

Interaction between valproate formulation and phenytoin concentrations

Suzuki

Nagai

Mano

et al. 1995

Eur J Clin Pharmacol

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Changes in phenytoin concentrations caused by switching valproate formulations with different absorption rates were retrospectively investigated in eleven epileptic patients receiving treatment with both drugs. Total plasma phenytoin concentrations were measured before and after a standard tablet of valproate was replaced by the same dose as a slow-release tablet. The mean plasma phenytoin level rose significantly from 14.4 to 18.7 micrograms.ml-1. Nine of eleven patients had markedly increased phenytoin levels (by 21 to 72%), and two developed toxic symptoms. The results indicate that changing valproate formulations can cause major alterations in the plasma concentration of co-administered phenytoin.

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Valproic acid and plasma levels of phenytoin

Cited by 29 publications

References 0 publications

Valproic acid and diazepam interaction in vivo.

Valproic acid and diazepam interaction in vivo.

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

Interaction between valproate formulation and phenytoin concentrations

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