Valproate/valproic acid administration

Absorption - /a pro c acid is rapidly and almost completely absorbed from the Gl tract. Absorption of the drug is delayed but not decreased by administration with meals administration of the drug with milk products does not affect the rate or degree of absorption. The bioavailability of valproate from divalproex sodium delayed-release tablets and capsules containing coated particles has been shown to be equivalent to that of valproic acid capsules. 

The sodium salt of valproate is marketed in Europe as a tablet and is quite hygroscopic. In Central and South America, the magnesium salt is available, which is considerably less hygroscopic. The free acid of valproate was first marketed in the USA in a capsule containing corn oil the sodium salt is also available in syrup, primarily for pediatric use. An enteric-coated tablet of divalproex sodium is also marketed in the USA. This improved product, a 1 1 coordination compound of valproic acid and sodium valproate, is as bioavailable as the capsule but is absorbed much more slowly and is preferred by many patients. Peak concentrations following administration of the enteric-coated tablets are seen in 3-4 hours. Various extended-release preparations are available not all are bioequivalent and may require dosage adjustment. 

An enteric-coated tablet of divalproex sodium is also marketed in the USA. This improved product, a 1 1 coordination compound of valproic acid and sodium valproate, is as bioavailable as the capsule but is absorbed much more slowly and is preferred by most patients. Peak concentrations following administration of the enteric-coated tablets are seen in 3-4 hours. 

The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (14). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When... 

Each simulation included 100 hypothetical subjects. The model parameters used were derived from an adult population and there were no covariate distribution models for the virtual trial population. Subjects were assumed to be healthy and on valproate monotherapy (31). The simulations assumed that the extended release (ER) formulation was administered once daily and the delayed release (DR) preparation was administered twice daily. Unbound and total valproic acid concentrations were simulated from the time of dose administration to 280 h and the simulations were based on the administration of 1000 mg ER once daily, 500 mg DR twice daily, 2500 mg ER once daily, and 1000 mg DR twice daily. For once-daily regimens, simulation scenarios included doses taken 6, 12, 18, and 24h late from schedule and then two doses taken 24h late (replacement dose for the missed dose). For the twice-daily regimens, doses were simulated 3,6,9, and 12 h later than the scheduled times and then two doses were simulated 12 h later than scheduled to mimic replacement dosing for a missed dose. More extreme cases where two doses are delayed at various times or missed were also simulated. 

Importantly, its precise mechanism of its anticonvulsant action is still not fully understood. However, it has been duly advocated that its administration specifically inhibits GABA-transaminase, and thereby enhancing the concentration of cerebral GABA. It has also been observed that a few other straight-chain saturated fatty acids i.e., lower fatty acids, such as propanoic acid, butyric acid, and pentanoic acid which are devoid of anticonvulsant characteristic features are relatively more potent and efficacious inhibitors of GABA-transaminase than is valproic acid. Furthermore, it has been adequately substantiated that there exists a rather stronger correlation between the anticonvulsant potency of valproate and other branched-chain fatty acids besides, their capability to minimise the prevailing concentration of cerebral aspartic acid (an amino acid). 

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