Decreased plasma protein binding of valproate in patients with acute head trauma.

Abstract

1. One hundred and ten plasma samples were obtained from 50 patients treated with valproate for prophylaxis of post‐traumatic head injuries. The samples were selected to include a wide range of albumin concentrations and were assayed for free and total valproate concentrations. Valproate binding parameters were determined from the Scatchard equation for one binding site using reweighted least squares analysis. 2. Plasma albumin concentrations were measured in 130 patients with head trauma. They started to decrease immediately after trauma, reaching a minimum at 5‐7 days of approximately 24% of baseline value and did not return to normal until 1 month. 3. The free fraction of valproate varied six to seven‐fold as albumin concentration ranged from 1.5 to 4.8 g 100 ml‐1 (218‐696 mumol l‐1). The mean association constant for binding (Ka) was 0.008 mumol l(‐1) and the mean number of binding sites (N) was 2.0. There values were similar to those reported for valproate in otherwise healthy patients with epilepsy. 4. Because of saturable protein binding of valproate, hypoalbuminaemia may necessitate the monitoring of free valproate concentrations to avoid toxicity when valproate is used in patients with acute head injury.

Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model

“…Increased hepatic metabolism and decreased plasma protein binding result in an increase in the clearance and decreased concentrations of both unbound and bound drugs (9,10). The increase in hepatic metabolism has been shown to be relatively non-specific, affecting drugs metabolized by a diverse group of hepatic enzymes including various cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) isozymes.…”

IN VITRO CHARACTERIZATION OF LAMOTRIGINEN2-GLUCURONIDATION AND THE LAMOTRIGINE-VALPROIC ACID INTERACTION

“…[I] max was taken as the upper limit of the plasma VPA therapeutic range for the treatment of epilepsy; that is, 100 mg/l (693 M) (Dutta et al, 2003 unbound in blood (f u(VPA) ), which was taken as 0.1 (Anderson et al, 1994). Because VPA is essentially completely absorbed from the gastrointestinal tract, f a is 1.0 (Bressolle et al, 1994).…”

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

“…There is significant interindividual variability in VPA blood concentrations . Several studies illustrated that VPA's clinical pharmacokinetic evaluation based on total drug concentration may be misleading as a result of reduced protein binding, saturable protein binding, and saturable metabolism . Unbound VPA clearance decreases with increasing VPA serum concentration, particularly in the elderly .…”