Valproic acid plasma concentrations

M. Ki ogh, K. Johansen, F. Tonnesen and K. E. Rasmusen, Solid-phase microexti action for the detemination of the free concentration of valproic acid in human plasma by cap-illai y gas chi omatography , J. Chromatogr. B 673 299-305 (1997). 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Sodium valproate is converted to valproic acid in the intestine and the acid is absorbed. Absorption may be delayed by food or by enteric-coated tablets. Valproic acid has a low volume of distribution and high plasma protein binding. In the elderly there is a risk for increased free valproic acid concentrations requiring lower doses and plasma concentrations at the lower therapeutic range. However it should be realized that these plasma concentrations do not correlate very well with the therapeutic or toxic effects and careful observation for symptoms is mandatory. 

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. 

For some agents for example valproic acid and ethanol, a threshold concentration must be reached before teratogenicity is induced and the effect is therefore related to the maximum plasma concentration For others such as retinoids and cyclophos-... 

The distribution of DVP appears to be restricted to plasma and rapidly exchangeable extracellular water (AHFS, 2000). The volume of distribution is 0.26 L/kg in children and 0.19 L/kg in adults (AHFS, 2000). The half-life is 7.2 2.3 hours in children and 13.9 3.4 hours in (healthy) adults (Levy et al., 1984). Valproic acid has been detected in CSF (approximately 10% of serum concentrations) and milk (about 1%-10% of plasma concentrations). The drug crosses the placenta. Valproic acid may displace other drugs from proteinbinding sites. 

Ko GN, Korpi ER, Freed WJ, et al. Effect of valproic acid on behavior and plasma amino acid concentrations in chronic schizophrenia patients. Biol Psychiatry 1985 20 199-228. 

Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit 1999 21(3) 341-5. 

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... 

PLATINUM COMPOUNDS ANTIEPILEPTICS -CARBAMAZEPINE, PHENYTOIN, VALPROIC ACID l plasma concentrations of antiepileptic, which t risk of seizures Due to impaired absorption of antiepileptic Monitor closely for seizure activity and warn patients and carers. Need to adjust dosage using parameters such as blood levels to ensure therapeutic levels... 

Toxicity. Plasma concentrations greater than 200 o.g/ml are associated with toxic effects but valproic acid is relatively nontoxic after overdose, and recovery after the ingestion of up to 75 g has been reported. Hepatotoxicity has been reported during therapeutic administration. 

The rationale and use of modified-release formulations of antiepileptic drugs (carbamazepine, valproic acid, and tiagabine) have been reviewed (171). The authors concluded that modified-release formulations afford the advantages of better patient compliance, fewer adverse effects, and less fluctuation in plasma concentrations, making monitoring of drug concentrations easier. They concluded that these advantages should lead to better seizure control and improved quahty of life. 

Plasma protein binding interactions are usually clinically unimportant, but they should be recognized, because they alter the relation between serum drug concentration and the clinical response if displacement occurs, therapeutic and toxic effects are reached at a total drug concentration lower than usual. For example, valproic acid and salicylate displace phenytoin from plasma proteins this usually results in a fall in total phenytoin concentration without any change in the concentration of unbound (pharmacologically active) phenytoin. 

De Turck BJ, Diltoer MW, Cornehs PJ, Maes V, Spapen HD, Camu F, Huyghens LP. Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin. J Antimicrob Chemother 1998 42(4) 563-4. 

Plasma concentrations of antiepileptic drugs (for example carbamazepine, valproic acid, phenytoin) should be measured more frequently during cisplatin-containing cancer chemotherapy (266,267). 

Thrombocytopenia can be caused by autoimmune mechanisms (SED-13, 150) (54), tends to be related to high serum drug concentrations, and often responds to dosage reduction (SEDA-19, 74). Of 131 patients randomized to high plasma concentrations of valproic acid (80-150 gg/ml), 36 (27%) had at least one platelet count below 75 X 10 /1, compared with only one patient in a group randomized to drug concentrations of 25-50 gg/ml (55). 

After a valproate overdose a 27-year-old man developed seizures, hypernatremia, respiratory failure, metabolic acidosis, liver failure, and bone marrow depression (125). His plasma valproic acid concentration was 1414 pg/ml. Treatment with hemodialysis was effective in enhancing valproic acid clearance, while hemoperfu-sion was relatively less effective, because of saturation of the column. Overall, the half-Ufe of the drug was reduced from over 20 hours before treatment to less than 3 hours during hemodialysis/hemoperfusion drug removal was probably favored by saturation of drug binding to plasma proteins, which resulted in a low unbound fraction (32% at the start of treatment). He was comatose for 5 days but recovered fully thereafter. 

Serum phenytoin concentrations can be increased or reduced by valproate (138) since valproic acid displaces phenytoin from plasma proteins, therapeutic and toxic effects of phenytoin occur at total phenytoin concentrations lower than usual. 

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. 

Kojima S, Nadai M, Kitaichi K, Wang L, Nabeshima T, Hasegawa T. Possible mechanism by which the carba-penem antibiotic panipenem decreases the concentration of valproic acid in plasma in rats. Antimicrob Agents Chemother 1998 42(12) 3136-40. 

Renal disease (uraemia) may increase the volume of distribution of acidic drugs that extensively bind to plasma albumin (e.g., phenytoin, valproic acid, naproxen, phenylbutazone, furosemide). As decreased protein binding would increase the unbound (free) fraction in the plasma, the therapeutic concentration range (based on total drug concentration) would be lower than the usual... 

For drugs with short half-lives (30 min to 3 h) and a relatively narrow margin of safety, the use of an inconveniently short dosage interval (< 6 h) would be required to maintain plasma concentrations within the therapeutic range. This situation applies to carbamazepine and valproic acid (anticonvulsants), which are commercially available as conventional oral dosage forms. For drugs with a... 

Valproic Acid. Valproic acid (VPA), is available in several chemical forms, including valproic acid, sodium valproate, and divalproex sodium, a stable coordination compound containing equal proportions of valproic acid and sodium valproate. In either of these forms, the dosage is expressed as valproic acid equivalents (Table 6.1) (18).Oral valproic acid derivatives are rapidly absorbed the absolute bioavailability of divalproex extended-release (ER) tablets was about 90% relative to that of the intravenous infusion. The ER form had an average bioavailability of 81 -89%compared to that of divalproex delayed-release tablets given twice daily. The relationship between plasma concentration and clinical response is not clear. This may be attributed to the nonlinear concentration-dependent protein binding of valproic acid, which in turn affects the clearance of the agent (18). 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

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