Free Fraction Of Valproic Acid Research Articles

Pharmacokinetics of valproic acid in the elderly.

The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.

Protein binding of valproic acid in maternal and umbilical cord serum.

The serum valproic acid levels of 18 maternity patients at the time of delivery were compared with the valproic acid levels in the umbilical cord serum. The levels in the umbilical cord serum were 1.1-4.6 times higher than those in the maternal serum, with a mean value of 1.38. One explanation for this difference apparently is an increased protein binding of valproic acid in the infant's serum. Protein binding was determined in nine patients, in six by equilibrium dialysis and in three by ultrafiltration. The median value of the free fraction of valproic acid was 9.1% (range, 5.8-16.4%) in the umbilical cord serum (equilibrium dialysis) and 15% (range, 12.7-35.3%) in the maternal serum. The difference between the infant and the maternal serum is significant.

A longitudinal study of valproate free fraction in the specific age group at greatest risk for febrile convulsions (children below 3 years).

The behavior of the free fraction of valproic acid (VPA) was evaluated during long-term treatment of 24 children (9-18 months of age) with febrile convulsions. A series of relevant hematological parameters was monitored for the entire observation period (12 months). VPA plasma levels ranged from 54.3 +/- 26 to 66.6 +/- 32.8 micrograms/ml. The unbound fraction of the drug was determined in tears, which has been shown to be the best practical indicator of the free portion of an anticonvulsant drug, and ranged from 5.1 +/- 4.0 to 6.1 +/- 4.3 micrograms/ml. The tear/plasma ratio (and hence the free/total ratio) ranged from 9.3 to 9.7, in agreement with literature data. No significant variations of VPA plasma and tear levels, and therefore of the tear/plasma ratios, were ever observed. The hematological data revealed no significant alterations during the entire observation time, although some of the variables did fluctuate. Side effects were mild and temporary. The present report indicates that VPA has no particular toxic effect in young children treated for the prevention of febrile convulsions.

Mechanism of altered drug binding to serum proteins in pregnant women: studies with valproic acid.

The mechanism underlying the impaired serum protein binding of valproic acid (VPA) in pregnancy was examined in samples collected from 24 healthy women in the last 3 weeks of gestation and 15 age-matched nonpregnant female controls. Experiments were performed in vitro using a rapid equilibrium dialysis technique free from in vitro alterations in free fatty acids (FFA). At a total drug concentration of approximately 420 mumol/L, the free VPA fraction was 10.2 +/- 2.9% (SD) in pregnant women and 4.8 +/- 1.0% in controls (p less than 0.001). Pregnancy was associated with a marked reduction in serum albumin levels but with only a slight, nonsignificant elevation in FFA. Free VPA fraction was negatively correlated with serum albumin levels. A positive correlation between free VPA fraction and FFA was observed in the pregnant group but not in the controls. The only sample collected during labour showed a striking elevation of both free VPA fraction and FFA, in spite of a normal albumin concentration. Scatchard's plots showed VPA bound to two classes of binding sites on the albumin molecule. The number of primary (n1) and secondary (n2) binding sites in pregnant women (n1 = 2.0; n2 = 10.7) was virtually identical to that observed in the controls (n1 = 1.9; n2 = 9.8). The association constants of the primary (k1) and secondary (k2) sites were lower in pregnant women (15.9 X 10(3) and 0.19 X 10(3) L/mol, respectively, vs. 22.6 X 10(3) and 0.33 X 10(3) L/mol in controls) but the difference was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Free fraction of valproic acid is the same in serum and plasma.

Journal Article Free fraction of valproic acid is the same in serum and plasma. Get access J A Cramer, J A Cramer Search for other works by this author on: Oxford Academic Google Scholar K A McCarthy, K A McCarthy Search for other works by this author on: Oxford Academic Google Scholar R H Mattson R H Mattson Search for other works by this author on: Oxford Academic Google Scholar Clinical Chemistry, Volume 29, Issue 7, 1 July 1983, Page 1449, https://doi.org/10.1093/clinchem/29.7.1449 Published: 01 July 1983

Diurnal fluctuations in free and total plasma concentrations of valproic acid at steady state in epileptic patients.

The diurnal fluctuations in free and total plasma concentrations of valproic acid (VPA) were determined by taking serial blood samples at 2-h intervals in six epileptic patients receiving maintenance therapy with sodium valproate (9.6-24.0 mg/kg in three divided daily doses). Both the free and the total concentrations fluctuated markedly during the period examined (0800-1800 h). The fluctuation of the free drug was about twice as great as that of the total drug (79 +/- 27% versus 47 +/- 21%, p less than 0.01). There was a considerable inter- and intrapatient variability in free VPA fraction. In at least four of six patients the free fraction increased in proportion to the increase in total concentration. These findings are in line with available evidence that the binding of VPA to plasma proteins is saturable within the clinically occurring concentration range. The changing and unpredictable relationship between total and free concentration suggests that VPA therapy can be monitored more rationally by measuring the free drug.

Free fraction of valproic acid: in vitro time-dependent increase and correlation with free fatty acid concentration in human plasma and serum.

The effect of sample incubation and storage on the protein binding of the antiepileptic drug valproic acid (VPA) and on the concentration of free fatty acids (FFA) was investigated in serum and plasma collected from four normal volunteers. Both the free fraction of VPA and the concentration of FFA increased progressively with time when samples were incubated at 4 to 37 degrees C. These effects occurred to the same extent in both serum and heparinized plasma. At 4 degrees C and at room temperature, the increase in free drug fraction was relatively small (18 and 25% respectively at 24 h), whereas at 37 degrees C it was quite considerable (24% at 8 h and 40% at 24 h). At room temperature, FFA rose on average by 22% at 4 h, 34% at 8 h, and 86% at 24 h, whereas at 37 degrees C the increases at the same incubation times were 59, 90, and 160%, respectively. There was a strong positive relationship between changes in free VPA fraction and FFA content of the samples. The time-dependent changes in VPA binding capacity described in this study may lead to overestimation of the actual free concentration in vivo, especially when this is estimated by equilibrium dialysis or ultracentrifugation techniques requiring long incubation (centrifugation) times at 37 degrees C.

Determination of unbound valproic acid concentration in plasma by equilibrium dialysis and gas--liquid chromatography: methodological aspects and observations in epileptic patients.

An equilibrium dialysis technique for the separation of the free (unbound) concentration of valproic acid (VPA) in plasma is described together with a sensitive gas chromatographic assay for the quantitative determination of the drug in the dialysate. The overall coefficient of variation of the method was below 10%. By using a high permeability membrane, equilibration of the drug between the plasma and the buffer compartments was obtained after about 45 min at 37 degrees C. With this dialysis time, dilutional changes in the plasma compartment were negligible and there was no significant change in the plasma-free fatty acid (FFA) concentration. No passage of protein into the buffer solution was detected. When dialysis was prolonged for up to 4 h, a significant elevation in plasma FFA (with a corresponding rise in free VPA fraction) was observed. Storage of plasma samples at temperatures ranging from 4 to 37 degrees C for 8 h or longer before dialysis also resulted in an increased value of free VPA fraction and FFA concentration. The two effects were significantly correlated. The free fraction of VPA was found to increase with increasing total plasma concentration. This effect was observed both in vitro and in vivo in the plasma of 91 patients receiving chronic VPA therapy. The methodological problems of using equilibrium dialysis techniques for determining the free fraction of VPA are highlighted.

The free fraction of valproic acid in tears, saliva, and cerebrospinal fluid.

Valproic acid (VPA) was determined by EMIT assay in plasma, tears, saliva, and cerebrospinal fluid (CSF) of patients with epilepsy. Closer correlation was shown between tear/plasma and tear/CSF ratios than between saliva/plasma and saliva/CSF ratios. The VPA CSF/serum ratio was in good agreement with data in the literature. Salivary levels were extremely erratic, while those for tears were much more reliable. Determination of VPA in tears is therefore the best method of studying the VPA free fraction in those cases in which investigations of protein binding of the drug are necessary.

Effect of phenytoin on protein binding of valproic acid.

In vitro experiments using the equilibrium dialysis technique were performed to determine the binding of valproic acid to plasma components in the absence and presence of therapeutic concentrations of phenytoin. The free fraction of valproic acid was found to be dependent on the total valproic acid concentration. Phenytoin did not influence valproic acid protein binding.