Valproic acid binding

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. 

An understanding of absorption, binding, metabolism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, triiodothyronine, valproic acid, sulfafurazole, and salicylic acid. 

Cloyd, J.C., Fischer, J.H., Kriel, R.L., and Kraus, D.M. (1993) Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 53 22-29. 

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... 

The interaction between proteins and a drug is governed by the law of mass action, in that the proportion of bound drug remains constant, provided the binding sites are not saturated. With the possible exception of valproic acid and disopyramide, the saturability of binding sites does not occur within therapeutic ranges. 

Barre J, Chamourad JM, Houin G, Tillement JP (1985) Equilibrium Dialysis, Ultrafiltration and Ultracentrifugation Compared for Determining the Plasma-Protein Binding Characteristics of Valproic Acid. Clinical Chemistry... 

The use of protein-coated acoustic wave devices for detection of gas-phase species has also been reported with claims of good sensitivity and selectivity. Guilbault et al. reported TSM sensors for the reversible gas-phase detection of formaldehyde [227], and organophosphorous pesticides [228,229]. More recent studies have cast some doubt as to whether the gas-phase sensitivity was the result of selective immunochemical binding, or simply due to nonspecific adsorption. In work reported by Thompson et al. [230], sensors coated with parathion antibody exhibited sensitivities to the pesticides parathion, malathion, and disul-foton that were remarkably similar to sensors coated with nonspecific proteins (valproic acid antiserum, human immunoglobulin G, and bovine serum albumin). The fact that the previous study [228] reported significantly larger sensitivity at... 

In the elderly, a small decrease in albumin concentration is associated with a small decrease in binding for salicylate, diazepam, phenylbutazone and valproic acid. Also in the elderly, an increase in concentration of AAG is associated with an increase in binding of AAG-bound drugs. Such an increase in AAG concentrations could be related to the greater incidence of inflammatory diseases in this population. 

Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. Interaction between valproic acid and aspirin in epileptic children serum protein binding and metabolic effects. Clin Pharmacol Ther 1982 31(5) 642-9. 

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. 

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