Valproate sodium metabolism

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

I Pharmacokinetics. Valproate sodium is rapidly converted to valproic acid in the stomach, whereas divalproex sodium delayed-release and extended-release tablets must pass into the small intestine to be converted to valproic acid. Valproic acid is highly bound to albumin and other plasma proteins, and it is extensively metabolized in the liver. A summary of the absorption, distribution, metabolism, and elimination data for valproate is found in Table 68-11. ... 

Its meehanism of aetion may be related to inereased brain levels of the inhibitory neurotransmitter Gamma-aminobutyric acid (GABA). This increase in brain content of GABA is probably due to the inhibition by valproate sodium of the enzymes that metabolize GABA. 

Further evidences reveal that valproate sodium may also deerease binding to eertain serum proteins or bloek the hepatic metabolism of phenobarbital. Therefore, administration of the drug to patients in a steady state, while on phenobarbital eoneurrently (or primidone, which gets metabolized to phenobarbital) may enhance the plasma levels of phenobarbital from 35-200%, a quantum jump, thereby eausing an excessive somnolence. However, the present evidenee amply substantiates that this is caused exelusively by an immediate lowering in the prevailing rate of elimination of phenobarbital. 

Sodium valproate GM PM 6 also 1 Inhibition of GABA metabolism... 

Introduced initially for absence seizures, this drug is now known to be effective in and used to treat tonic lonic seizures and most types of epilepsy. It was found to inhibit GABA transaminase and so elevate GABA concentrations and inhibition. This is achieved, however, over a slower time-course than its anti-seizure effect, especially experimentally, which is now thought to be due to its phenytoin-like, use-dependent block of sodium channels. Since, unlike phenytoin, the full effect of valproate takes some weeks to develop, its slower effect on GABA metabolism and activity should not be ignored. 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

In 1976, Matsumoto, et. al. (17, 18) discovered several new metabolites of sodium valproate in rat urine, which support the hypothesis that the drug is also metabolized by a 6-oxidation mechanism. One of the metabolites, 2-n-propyl 3-oxo-pentanoic acid, was recently found by Gompertz, et. al. (19) and Kochen, et. al. (20) to be a major constituent in urine of children who were receiving sodium valproate. The urinary 3-oxo derivative of valproate was reported to account for 20% of the administered dose. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

Yuen AW, Land G, Weatherley BC, et al. Sodium valproate acutely inhib-itslamotrigine metabolism. Br J Clin Pharmacol 1992 33 511-513. 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

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... 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

Sodium valproate appears to be a nonspecific inhibitor and impairs the metabolism of phenytoin, phenobarbitone and primidone. 

Antiepileptics azapropazone and phenylbutazone inhibit the metabolism of phenytoin and sodium valproate, increasing their risk of toxicity. 

Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include sodium valproate, cimetidine, co-trimoxazole, isoniazid, chloramphenicol, some NSAIDs, disulfiram. There is a considerable body of mediocre and contradictory data, the lesson of which is that possible interaction should be borne in mind wherever other drugs are prescribed to a patient taking phenytoin. 

Sodium valproate is extensively metabolised in the liver and has a t / of 13 h. It is 90% bound to plasma albumin. Sodium valproate is a nonspecific inhibitor of metabolism, and indeed inhibits its own metabolism, and that of lamotrigine, phenobarbitone, phenytoin and carbamazepine. Sodium valproate does not induce drug metabolising enzymes but its metabolism is enhanced by induction due to other drugs, including antiepileptics. 

Metabolic inhibition by valproate prolongs the action of co-administered antiepilepsy drugs (see above). The effect is significant and the dose of lamotrigine, for example, should be halved in patients who are also taking sodium valproate. 

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction) the effect of phenytoin is variable. Clonazepam and sodium valproate are safe. 

Aspirin displaces sodium valproate from protein binding sites (112) and reduces its hepatic metabolism (113). 

Sodium valproate Aspirin Inhibition of valproate metabolism, increasing plasma concentration Avoid aspirin monitor plasma concentration if other NSAIDs are used... 

Sodium benzoate decreased urea production in ammonia challenged rats (Maswoswe et al. 1986) and hyperammonemic mice (O Connor et al. 1987). Valproate, a widely used antiepileptic dmg, has a hyperammonemic effect in Wistar rats (Ferrier et al. 1988) and may therefore predispose to ammonia intoxication. Ammonia interferes with the metabolism of pent-4-enoic acid in cultured rat hepatocytes and may dramatically potentiate its toxicity (Coude and Grimber 1984). 

The evidence suggests that carbamazepine increases the metabolism of valproate, so that it is cleared from the body more quickly. Carbamazepine may also possibly increase the formation of a minor but hepatotoxic metabolite of sodium valproate (2-propyl-4-pentenoic acid or 4-ene-... 

The latter stages of carbamazepine metabolism appear to be inhibited by both valproate and its amide derivative, valpromide. The levels of the metabolite earbamazepine-,10,11-epoxide increase during concurrent use, probably by inhibition of its metabolism to carbamazepine-10,11-trans-di-qI 28-30 jy epoxide hydrolase. Valpromide was found to be about 100 times more potent an inhibitor of this enzyme than sodium valproate in wtro and caused a threefold higher rise in epoxide levels than valproate in one study. The carbamazepine-10,11-epoxide metabolite has antieonvulsant activity, but it may also cause toxicity if its serum levels beeome exees-sive. ... 

Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism, BrJ Clin Pharmacol (1992) 33,511-13. 

The clearance of caffeine was about twofold higher and its half-life was reduced by about 50% in patients with epilepsy taking phenytoin, when compared with healthy subjects not taking any medications. In the same study, there were no significant differences in caffeine pharmacokinetics between healthy subjects and patients receiving carbamazepine or sodium valproate. Conversely, carbamazepine was considered to have induced the metabolism of caffeine in 5 children with epilepsy, as assessed by the caffeine breath test. In another study in healthy subjects, there was a reduction in the AUC of carbamazepine when it was given with caffeine, but caffeine had no effect on the pharmacokinetics of sodium valproate. ... 

Chapman A G, Riley K., Evans M. C and Meldrum B. S. (1982) Acute effects of sodium valproate and y-vmyl GABA on regional ammo acid metabolism in the rat brain incorporation of 2- C-glucose into ammo acids. Neurochem Res 7, 1089-1105. 

Elmslie JL, Porter RJ, Joyce PR, Hunt PJ, Shand BI. Scott RS Comparison of insulin resistance, metabolic s5mdrome and adipo-nectin in overweight bipolar patients taking sodium valproate and controls. Aust N Z J Psychiatry 2009 43(1) 53-60. 

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