Valproic acid, inhibition

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

Michaelis M, Michaelis UR, Fleming 1, Suhan T, Cinatl J, Blaheta RA, Hoffmann K, Kotchetkov R, Busse R, Nau H, Cinatl J Jr (2004) Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol 65 520-527... 

Other compounds producing some inhibition of ZDV conjugation were oxazepam, salicylic acid, and acetylsalicyclic acid. More recently, Trapnell et al. examined the inhibition of ZDV at a more relevant concentration of 20 pM in bovine serum albumin (BSA)-activated microsomes by atovaquone, methadone, fluconazole, and valproic acid at therapeutically relevant concentrations (127). Both fluconazole and valproic acid inhibited ZDV glucuronidation by more than 50% at therapeutic concentrations. Clinical interaction studies have been conducted with methadone, fluconazole, naproxen, probenecid, rifampicin, and valproic acid (see Table 10). 

Porubek DJ, Grillo MP, Olsen RK, et al. Toxic metabolites of valproic acid inhibition of rat liver acetoacetyl-CoA thiolase by 2-n-propyl-4-pentenoic acid (A4-VP A) and related branched chain carboxylic acids. In Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanisms of Toxicity. New York Raven Press, 1991 53-58. 

At a concentration of 100 gg/ml, valproic acid inhibits the glucuronidation of zidovudine in human liver microsomes by 50% (143). This observation explains the previously reported effect of valproate to increase plasma zidovudine concentrations in HIV-infected patients. 

Valproic acid inhibits the metabolism of drugs that are substrates for CYP2C9, including pheny-toin and phenobarbital. Valproic acid also inhibits UGT and thus inhibits the metabolism oflam-otrigine and lorazepam. Valproic acid is highly bound to albumin and can displace phenytoin and other drugs this displacement can exacerbate valproic acid s inhibition of phenytoin metabolism. 

Valproic acid In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of phenytoin, phenobarbital, and lamotrigine. Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug. 

Valproic acid often causes gastrointestinal distress and is potentially hepatotoxic. The use of this drug in pregnancy has been associated with teratogenicity (neural tube defects). Valproic acid inhibits the metabolism of barbiturates marked CNS depression may result if such drugs are given concomitantly. Peripheral neuropathy, in the form of diminished deep tendon reflexes in the lower extremities, is associated with chronic use of phenytoin. The answer is (C). 

Valproic acid Inhibits histone acetylase activity Huangfu et al. (2008)... 

Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations ofthe 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant. 

The most frequent side effects are diplopia, drowsiness, ataxia, and headache. Rashes are usually mild to moderate, but Stevens-Johnson reaction has also occurred. The incidence of the more serious rashes appears to be increased in patients who are also receiving valproic acid and who have rapid dosage titration. Valproic acid substantially inhibits the metabolism of lamotrigine. 

Ethanol increases phenobarbital metabolism, but valproic acid, cimeti-dine, and chloramphenicol inhibit its metabolism. 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

All four members of this class of HDAC have been demonstrated to be sensitive to HDAC-specific inhibitors (HDACi) such as trichostatin A (TSA). It is noteworthy that the HDACi Valproic acid (VPA), in addition to selectively inhibiting the catalytic activity of class I HDACs, induces proteasomal degradation of HDAC2, in contrast to other inhibitors such as TSA (Kramer et al, 2003). 

One of the first HDAC inhibitors to be identified and characterized was sodium butyrate, where it was found to alter the histone acetylation state (Riggs et al, 1977), and further determined to inhibit HDAC activity both in vitro and in vivo (Candido et al, 1978). Almost a decade later trichostatin A (TSA), a fungistatic antibiotic, was found to induce murine erythroleukemia cell differentiation (Yoshida et al, 1987). To date, a wide range of molecules have been described that inhibit the activity of Class I and Class II HDAC enzymes, and with a few exceptions, can be divided into structural classes including (1) small-molecule hydroxamates, such as TSA, suberoylanilide hydroxamic acid (SAHA), scriptaid and oxamflatin (2) short-chain fatty-acids, such as sodium butyrate, sodium phenylbutyrate and valproic acid (VPA) (3) cyclic tetrapeptides, such as apicidin, trapoxin and the depsipeptide FK-228 and (4) benzamides, such as MS-275 and Cl-994 (for reviews see Remiszewski et al, 2002 Miller et al, 2003). Some of these molecules are represented in Fig. 4. 

Of the many drugs that have been developed which modulate GABA function, the inhibitors of GABA transaminase have been shown to be effective anticonvulsants. These are derivatives of valproic acid that not only inhibit the metabolism of GABA but may also act as antagonists of the GABA autoreceptor and thereby enhance the release of the neurotransmitter. GABA-uptake inhibitors have also been developed (for example, derivatives... 

Valproic acid and its salts are a new group of antiepileptic drugs that differs from the known drugs both structurally and in terms of its mechanism of action. It is believed that it acts on the metabolism of the GABA system. Valproic acid has been shown to elevate the level of GABA in the brain by means of competitive inhibition of GABA transaminase and the dehydrogenase of succinic semialdehyde. 

Impairment of mitochondrial jj-oxidation leads to accumulation of fat, resulting in steatosis. Examples are various tetracycline derivatives, valproic acid (used to treat seizures) and overdoses of aspirin [64—66]. Certain NSAIDs such as ibuprofen, ketoprofen and naproxen also have the ability to inhibit jj-oxidation [67-69]. 

Valproic acid is a fatty acid derivative which is used for the management of absences and the control of generalized tonic-clonic seizures. Multiple mechanisms of action have been proposed. It prolongs Na+ inactivation which could explain its effectiveness against grand mal seizures. However also inhibition of T-Type Ca++ channels has been postulated. 

Type II Multiple actions enhance GABAergic inhibition, reduce T-calcium currents, and possibly block SRF Valproic acid Benzodiazepines Phenobarbital Primidone... 

Mortensen, P.B., Kolvraa, S. and Christensen, E. (1980) Inhibition of the glycine cleavage system hyperglycmemia and hyperglycinuria caused by valproic acid. Epilepsia 21 563-569. 

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