Valproate protein binding

When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion. 

Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember that the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for different drugs. 

The drug is highly bound to albumin (approximately 90%) [91]. Protein binding is concentration dependent and decreases at high valproate concentration [91]. Free fraction plasma protein concentration increases from approximately 10% at 40 pg/mL to 18.5% at 130 pg/mL [91], Protein binding decreased markedly in elderly [92], in patients with renal failure [92], and in liver diseases [93]. 

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). 

Nakashima, M., Takeuchi, N., Hamada, M., Matsuyama, K., Ichikawa, M. and Goto, S. (1994) In vivo microdialysis for pharmacokinetic investigations a plasma protein binding study of valproate in rabbits. Biolo ccd el Pharmaceutical Bulletin, 17, 1630-1634. 

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. 

It is difficult to establish a relation between valproate encephalopathy and increased serum ammonium concentrations. Valproate-induced hyperammonemic encephalopathy has been reported in several single case reports, but still it is difficult to ascertain whether hyperammonemia or valproic acid is the cause of the encephalopathy. In one case valproate was used in combination with lithium, which in itself could have caused encephalopathy by displacement of protein binding or other mechanisms, regardless of hyperammonemia (1181). In a second case it was also impossible to evaluate the effect of hyperammonemia on the level of consciousness, since it involved a woman who took valproic acid (30 g) in addition to... 

Clearance for valproate is low its half-life varies from 9 hours to 18 hours. At very high blood levels, the clearance of valproate is dose-dependent. There appear to be offsetting changes in the intrinsic clearance and protein binding at higher doses. Approximately 20% of the drug is excreted as a direct conjugate of valproate. 

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. 

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

Valproate Carbamazepine epoxide Diazepam Felbamate Lamotrigine Phenobarbital Risk of toxicity, particularly with phenobarbital including primidone-derived phenobarbital and lamotrigine Inhibition of metabolism of the affected drug. Valproate also displaces diazepam from protein binding sites, affecting relation between total diazepam concentration and effect... 

Naproxen Valproate Interaction of little or no clinical significance Displacement from plasma protein binding sites... 

Phenylbutazone Phenytoin Valproate Risk of toxicity, particularly with phenytoin altered relation between total concentration and effect Displacement from plasma protein binding sites and inhibition of metabolism of the affected drugs... 

Inconclusive evidence suggests that salicylic acid can potentiate valproate toxicity (mechanism unclear). Sulfafurazole, sulfamethoxypyridazine, possibly other sulfonamides, and sulfinpyrazone displace phenytoin from plasma protein binding sites with different affinities total phenytoin concentrations may underestimate the concentration of unbound (pharmacologically active) drug. 

The pharmacokinetic interaction of phenytoin with valproate is complicated (78-80). Initially, the total serum phenytoin concentration falls, because valproate displaces phenytoin from protein binding sites and so the unbound fraction increases, with a consequent increase in clearance. Because of the change in unbound fraction the total plasma concentration effect curve is shifted to the left, and a lower total concentration is as effective as the total phenytoin concentration was in the absence of valproate. However, valproate also inhibits the metabolism of phenytoin and so the serum phenytoin concentration then starts to rise and there is a risk of toxicity. 

Non-linear protein binding of valproate can result in disproportionate increases in unbound drug adverse effects can then result when dosage adjustments are based solely on measurement of total valproate serum concentrations in patients with hjrpoalbuminemia. 

Loscher, W. (1978) Serum protein binding and pharmacokinetics of valproate in man, dog, rat and mouse. Journal of Pharmacology and Experimental Therapeutics, 204, 255-261. 

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). 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

Children given antipyretic doses of aspirin co-administered with valproate were found to exhibit a decrease in protein binding and an inhibition of the metabolism of valproate. The common use of aspirin should alert to the need for caution if these drugs are co-administered. Interaction with other non-steroidal anti-inflammatory drugs (NSAIDs) may not be so prominent. 

Succinimides are indicated for the monotherapy of absence seizures or with concomitant therapy when additional forms of seizures occur in combination with absence seizures. These drugs are readily absorbed from the gastrointestinal tract and display very low protein binding. The drug interactions for the succinimides are less extensive than with the oxazolidinediones. They may increase plasma phenytoin levels, decrease plasma primidone levels, and either increase or decrease valproate levels, although the changes may not be clinically significant. 

The initial fall in total serum phenytoin levels appears to result from the displacement of phenytoin from its protein binding sites by valproate, the extent being subject to the diurnal variation in valproate levels. This allows more of the unbound drug to be exposed to metabolism by the liver and the total phenytoin levels fall. After several weeks the metabolism of the phenytoin is inhibited by the valproate and phenytoin levels rise. This may result in sustained elevation of free (active) phenytoin levels. Phenytoin reduces valproate levels, probably because it increases its metabolism by the liver. Because phenytoin is an enzyme inducer it may also possibly increase the formation of a minor but hepatotoxic metabolite of valproate (2-propyl-4-pentenoic acid or4-ene-VPA). ... 

Valproate toxicity developed in three patients given large and repeated doses of aspirin. Increased levels of free valproate were found in S children within hours of them taking aspirin. Con-versefy, a slightly reduced valproate level was reported in one patient who took ibuprofen. Modestly altered protein binding has been shown when sodium valproate was given with diflunisal or naproxen, but this appears unlikely to be clinically important... 

Aspirin displaces valproate from its protein binding sites and also alters its metabolism by the liver so that the levels of free (and pharmacologically active) valproate rise. This could temporarily increase both the therapeutic and toxic effects of the valproate. However, there is evidence that increased hepatic elimination of valproate counterbalances this effect. 

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