Free and Total Serum Valproate Concentrations: Their Relationship to Seizure Control, Liver Enzymes and Plasma Ammonia in Children

Abstract

ABSTRACT:The relationships between total and free serum valproate (VPA) concentrations and seizure control, serum liver enzyme activity and plasma ammonia concentration were studied in 61 epileptic children. Enzymeimmunoassay (EMIT)R methods gave higher values of total VPA concentration than gas-liquid chromatography (GLC) methods. In over 80% of children with complete seizure control the ranges of total VPA concentration were 140-420 umol/L with GLC methods and 210-560 umol/L with EMIT methods. The range of free VPA concentrations in 78% of children with complete seizure control was 8.8-26.4 umol/L. Increased liver enzyme activity was observed in 6 of the 61 children and raised plasma ammonia concentration in 11 of 50 children. Plasma ammonia concentration was related to total serum VPA but was not related to free serum VPA. Increased serum liver enzyme activity was related to VPA dose per kg but not to free or total serum VPA concentration. Thus free VPA concentrations do not appear to be more useful than total VPA concentrations in predicting seizure control and do not correlate with liver enzyme activity or plasma ammonia concentration.

Is 2‐Propyl‐4‐Pentenoic Acid, a Hepatotoxic Metabolite of Valproate, Responsible for Valproate‐Induced Hyperammonemia?

“…Plasma NH, levels during VPA therapy have been reported to be dependent on serum VPA levels (Ohtani et al, 1982;Farrell et al, 1986). In our study, neither dosage nor serum level of VPA affected the plasma NH, level.…”

“…VPAinduced hyperammonemia is enhanced by concomitant use of other AEDs (Warter et al, 1983;Zac-cara et al, 1985;Ratnaike et al, 1986). Whether (Williams et al, 1984;Laub et al, 19866) the plasma ammonia (NH,) level is dependent on serum VPA levels (Ohtani et al, 1982;Farrell et al, 1986) is unknown.…”

Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both?

“…They disappear after reducing the dose of VPA or stopping TPM. There is no relationship between blood ammonia and VPA levels (Duarte et al, 1993;Farrell et al, 1986). The link between hyperammonaemia and encephalopathy has to be elucidated, knowing that asymptomatic hyperammonaemia without liver or renal disease is observed in 12% to 52% of the patients receiving VPA (Farrell et al, 1986;Murphy and Marquardt, 1982).…”

“…There is no relationship between blood ammonia and VPA levels (Duarte et al, 1993;Farrell et al, 1986). The link between hyperammonaemia and encephalopathy has to be elucidated, knowing that asymptomatic hyperammonaemia without liver or renal disease is observed in 12% to 52% of the patients receiving VPA (Farrell et al, 1986;Murphy and Marquardt, 1982). Hypotheses that might explain such interindividual differences would include an individual threshold above which the ammonaemia level in the brain alters consciousness, especially when its blood level rises rapidly (Zaccara et al, 1987), or blood-brain barrier permeability changes, both phenomena known to be more important in some Figure 6.…”

Extended-Release Formulations in Epilepsy

“…25,[27][28][29][30][31][32] In children, complete seizure control is obtained at lower valproic acid levels, between 20.2 and 50.5 µg/mL. 33 The therapeutic range is considered to be between 50 and 100 µg/mL of valproic acid.…”