Valproic acid enzymes

Decreased level of valproic acid enzyme induction Increased free level of valproic acid—risk of valproic acid toxicity... 

Most of the reported methods of analysis of valproic acid and its sodium salt in biological fluids rely on the use of chromatography, especially gas chromatography, although high performance liquid chromatography (HPLC) is also reported. Other methods, such as flow injection analysis, enzyme-immunoassay, fluorescence-polarization capillary electrophoresis, and potentiometry are sometimes used. The reported methods can be classified as follows. 

Five anticonvulsants including valproic acid were determined by the Abbott TD x fluorescence polarization immunoassay automatic analyzer. Recoveries were 94.8-106% and the coefficients of variations were 1.0-9.7% [23], Fluorescence polarization immunoassay and enzyme immunoassay were compared for the determination of free valproic acid in serum [24], Good correlation (R = 0.9992) was obtained between the two assays. Higgins [25] reported on the determination of valproic acid in serum by enzyme immunoassay with use of EMIT reagents and the Abbot ABA-200 analyzer. Responses were rectilinear up to 150 mg/L. 

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. 

At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-ene-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. At least 67 cases of hepatotoxicity have been reported, and most deaths were in mentally retarded children less than 2 years old who were receiving multiple drug therapy. 

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. 

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. 

Discontinuation of psychotropic drugs excluding valproic acid, carbamazepine, or other enzyme-inducing drugs After discontinuation of valproic acid After discontinuation of carbamazepine or other enzyme-inducing drugs... 

Younger children Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted valproic acid concentrations. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Valproic acid is metabolized in the liver and excreted in the urine mainly as glucuronide conjugates. Valproic acid is not an hepatic enzyme inducer. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Seizure control in patients receiving enzyme-inducing antiepileptic drug (ElAEDs), hut not valproic acid PO Recommended as add-on therapy 50 mg once a day for 2 wk, followed by 100 mg/day in 2 divided doses for 2 wk. Maintenance Dosage may be increased by 100 mg/day every week, up to 300-500 mg/day in 2 divided doses. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

Valproic acid, which is not an enzyme inducer, has no detectable effect on the pharmacokinetics of progestogens and estrogens (332). 

A major aim of enteric coating is protection of drugs that are sensitive or unstable at acidic pH. This is particularly important for drugs such as enzymes and proteins, because these macromolecules are rapidly hydrolyzed and inactivated in acidic medium. Antibiotics, especially macrolide antibiotics like erythromycin, are also rapidly degraded by gastric juices. Others, such as acidic drugs like NSAID s (e.g., diclofenac, valproic acid, or acetylsalicylic acid) need to be enteric coated to prevent local irritation of the stomach mucosa. 

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... 

ETOPOSIDE ANTIEPILEPTICS - PHENYTOIN, PHENOBARBITAL Significantly i plasma concentrations of etoposide (clearance may be >170%) and considerable risk of loss of therapeutic efficacy Due to potent induction of the hepatic microsomal enzymes that metabolize etoposide Do not co-administer. Consider use of alternative antiepileptics that do not induce hepatic microsomal enzymes, e.g. valproic acid... 

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