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PubMed1993

[Severe bone malformations in fetal valproic acid disease].

The dysmorphogenic and teratogenic effects of valproic acid, when administered to pregnant women, have been noted in several reports. We report the case of a 3-month-old infant with multiple congenital anomalies, including severe skeletal malformations, congenital heart defect and facial dysmorphism, whose mother was treated with valproic acid (1000 mg/day) throughout the pregnancy. This is the second published case reporting major skeletal malformations and supports the possible teratogenic effects of valproic acid.

Abnormalities, Drug-Induced↗
PubMed2005

Lower effectiveness of divalproex versus valproic acid in a prospective, quasi-experimental clinical trial involving 9,260 psychiatric admissions.

OBJECTIVE: The authors examined clinical differences between divalproex sodium and generic immediate-release valproic acid. METHOD: This 6-year prospective, quasi-experimental clinical trial compared the effectiveness and tolerability of divalproex and valproic acid. The dependent variables were length of hospital stay, rehospitalization rate, and adverse drug reactions in 9,260 psychiatric admissions. RESULTS: Inpatients who initially received divalproex sodium had a 32.7% longer hospital stay and 3.8% higher readmission rate than did patients who initially received valproic acid. Initial treatment with divalproex prolonged length of stay by 30.3% in patients treated with divalproex and valproic acid during different admissions. After other variables were controlled by multiway analysis of variance, the hospital stay of patients who continued the initial medication was 15.2% longer (2.0 days) for divalproex than valproic acid. Switching medications was more common for valproic acid, partly because of study design. Medication intolerance occurred in approximately 6.4% more patients taking valproic acid than divalproex. However, switching from valproic acid to divalproex did not significantly prolong length of stay, over that for continuous divalproex, or increase the rehospitalization rate. CONCLUSIONS: Lower peak valproate concentrations with divalproex sodium may have enhanced tolerability but may also explain the lower effectiveness. Extended-release divalproex could lower effectiveness further and require higher doses. Thus, inpatients are better served by beginning with generic valproic acid and by changing to delayed-release divalproex only if intolerance occurs. This would save up to one-third of inpatient costs and two-thirds of a billion dollars yearly in medication costs.

Adult↗
PubMed1980

Interactions of valproic acid with phenytoin.

The interaction of phenytoin and valproic acid was studied in four adults. We studied serial changes in total phenytoin concentrations, protein binding, urinary hydroxyphenylphenylhydantoin (HPPH) excretion, and half-life. In all four patients valproic acid caused an increase in the free fraction of phenytoin. Total phenytoin plasma concentrations decreased transiently in three patients and remained low throughout the study period in one patient. HPPH excretion increased transiently and then decreased, corresponding to changes in total phenytoin plasma concentrations. Biologic half-life transiently decreased in three patients (not statistically significant) and subsequently increased significantly in all four patients. The data suggest that valproic acid displaced phenytoin from protein-binding sites in all four patients and subsequently inhibited phenytoin metabolism in three patients.

Adult↗
PubMed1998

Elevated free phenytoin and free valproic acid concentrations in sera of patients infected with human immunodeficiency virus.

Seizures are common in patients infected with human immunodeficiency virus (HIV). Phenytoin and valproic acid are common anticonvulsants, and both drugs are strongly bound to serum albumin. Because patients infected with HIV are often on polytherapy, using homeopathic medicines, and may also have hypoalbuminemia, elevated free drug concentrations may occur in these patients. The authors prepared one serum pool from patients infected with HIV but receiving no bactrim and the other pool from HIV patients receiving bactrim. They supplemented both HIV pools and normal pool (diluted with 0.9% saline to mimic albumin concentration of HIV pools) with a known concentration of phenytoin or valproic acid. After incubation at 37 degrees C for 3 hours, they measured free phenytoin and free valproic acid concentrations in the protein free ultrafiltrates using fluorescence polarization immunoassays. The total drug concentrations in original sera were measured by microparticle enzyme immunoassays. None of the patients had any significant liver or renal disease. The aliquots of HIV pools and normal pool were supplemented with the same concentration of phenytoin or valproic acid. The concentration of free phenytoin and free valproic acid were significantly elevated in patients with HIV (mean = 2.52, SD = 0.11 micrograms/ml for phenytoin; mean = 41.5, SD = 1.5 micrograms/ml for valproate) compared to controls (mean = 1.50, SD = 0.0 7 micrograms/ml for phenytoin; mean = 19.9, SD = 0.5 micrograms/ml for valproate). The concentrations of both free phenytoin and valproic acid were further elevated in patients prepared in the HIV pool who were receiving bactrim (mean = 2.81, SD = 0.09 micrograms/ml for phenytoin; mean = 44.0, SD = 1.1 micrograms/ml for valproate), but when normal serum pool was supplemented with 4.4 mg/dl of bactrim (concentration of bactrim in HIV pool) and supplemented with the same concentration of phenytoin or valproic acid, the observed free concentrations were much lower (mean = 1.65, SD = 0.05 micrograms/ml for phenytoin; mean = 26.1, SD = 1.4 micrograms/ml for valproate). This indicates that hypoalbuminemia and bactrim concentrations do not account for the observed free drug concentrations in patients with HIV. The authors also observed elevated free phenytoin and valproic acid in sera from three individual patients with AIDS compared to normals (normal serum diluted with 0.9% saline to mimic the albumin concentration of serum collected from a patient with HIV and then both specimens supplemented with the same concentration of phenytoin or valproic acid.

Anticonvulsants↗
PubMed2002

Population pharmacokinetics of intravenous valproic acid in Korean patients.

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.

Adolescent↗
PubMed1978

[Valproic acid in the treatment of epilepsy with special emphasis on serum level determination (author's transl)].

Valproic acid has become a regular component of antiepileptic therapy. Generally it is used against genetically caused, primary generalized epilepsies with bilateral hypersynchronous neuronal discharges in the EEG. An improvement can also be observed by Valproic acid-treatment for secondary generalized and partial epilepsies. Therapeutic results could possibly be improved through a consideration of the serum concentration of valproic acid. Some of the commercial preparations contain the sodium salt of Valproic acid. The free acid which is quickly absorbed, is released in the stomach (tablet) or in the intestine (dragee). The half life is about 15 to 17 hours (one finds a range of 6 to 20 hours in the literature). In view of the half life, it is recommended that the daily dose should be divided into three single doses. About 84 to 95% of the substance is protein bound. Up to now, clinically relevant observations concerning the displacement of valproic acid from its protein binding are unknown. Recently in in vitro studies a decreased protein binding of valproic acid due to phenylbutazone, salicylic acid, and sulfadimethoxine and vice versa, a displacement of phenobarbital and phenytoin caused by valproic acid could be demonstrated. The therapeutic range of the serum level was between 50 and 120 mcg/ml. Individual patients showed that the dispensed dose did not reliably yield the expected serum levels. The necessary daily dose lies for adults between 600 and 2400 mg, in children between 15 and 150 mg/kg. The wide range of allowable dosis is dependent on whether or not valproic acid is to be given in conjunction with other antiepileptic drugs. When phenobarbital and valproic acid are given in conjunction one should be alert for a rise in the phenobarbital serum level. Results of studies in which valproic acid was combined with several other antiepileptic and psychotropic drugs are reported. The majority of the researchers determine a clear parallelism between clinical improvement and a normalization of the EEG in primary generalized epilepsies with bilateral synchronous 3/sec. spikes and waves. The background activity, determined by visual inspection, is not affected. Few workers discuss the correlation of the side effects of valproic acid and its serum level. Tiredness and impaired function of thrombocytes has been observed to be dependent on the valproic acid plasma level.

Blood Platelets↗
PubMed1979

Modification of phenytoin clearance by valproic acid in normal subjects.

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/- 0.17 v 0.38 +/- 0.11 ml min-1 kg-1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.

Adult↗
PubMed1998

Effect of carnitine on valproic acid concentrations in serum, brain, and liver.

This study investigates the influence of L-carnitine supplementation on valproic acid concentrations in rat serum, brain, and liver. Carnitine supplementation increased carnitine concentrations significantly in serum and liver but not in the brain. Free valproic acid concentrations in the brain were significantly increased by carnitine supplementation without any change of carnitine concentrations in the brain. The increase of serum-free valproic acid concentrations by carnitine supplementation apparently caused brain-free valproic acid concentrations to increase. This study suggests that L-carnitine supplementation to valproic acid therapy may potentiate valproic acid effects in the brain, even when the clinical dosage in humans is used.

Animals↗
PubMed1997

Population-based investigation of valproic acid relative clearance using nonlinear mixed effects modeling: influence of drug-drug interaction and patient characteristics.

Nonlinear mixed effects modeling (NONMEM) was used to estimate the effects of drug-drug interaction on valproic acid relative clearance values using 792 serum levels gathered from 400 pediatric and adult patients with epilepsy (age range, 0.3-54.8 years) during their clinical routine care. Patients received valproic acid as monopharmacy or in combination with either the antiepileptic drugs, phenobarbital, or carbamazepine. The final model describing valproic acid relative clearance was CL (mL/hr/kg) = 15.6.TBW (kg)-0.252.DOSE (mg/kg/day)0.183.0.898GEN.COPB.COCBZ, where COPB equals 1.10 if the patient is treated with phenobarbital, a value of unity otherwise, and COCBZ equals 0.769.DOSE (mg/kg/day)0.179 if the patient is treated with carbamazepine, a value of unity otherwise. Valproic acid relative clearance was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether valproic acid was administered alone or coadministered with phenobarbital or carbamazepine. When valproic acid was coadministered with phenobarbital or carbamazepine, valproic acid relative clearance increased as compared with that in monopharmacy. Its magnitude in the presence of carbamazepine increased in a valproic acid daily dose-related fashion. Concomitant administration of phenobarbital and valproic acid resulted in a 10% increase on valproic acid relative clearance. The clearance in female patients was approximately 10% less than that in male patients.

Adolescent↗
PubMed1991

Pharmacokinetics of valproic acid in guinea-pigs with biliary abnormality.

To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg-1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P less than 0.05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P less than 0.05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P less than 0.05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2.0 +/- 0.7 (s.e.m.) and 19.7 +/- 3.6 (s.e.m.)% of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.

Animals↗
PubMed2004

[Haemodialysis, L-carnitine therapy and valproic acid overdose].

We report the case of a severe valproic acid poisoning in a 36-year-old man. In front of a high serum concentration of valproic acid at the admission, haemodialysis was initiated to decrease serum valproic acid concentration. A L-carnitine therapy (50 mg/kg per day) was also started. A cerebral oedema appeared at the third day, but the patient recovered without any sequela.

Adult↗
PubMed1990

Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis.

Valproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C-labeled valproic acid (sodium-salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 microCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low-dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium.

Animals↗
PubMed2001

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9).

AIMS: To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. METHODS: Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1'-hydroxylase (CYP3A4). RESULTS: Valproic acid competitively inhibited CYP2C9 activity with a Ki value of 600 microM. In addition, valproic acid slightly inhibited CYP2C19 activity (Ki = 8553 microM, mixed inhibition) and CYP3A4 activity (Ki = 7975 microM, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time-, concentration- and NADPH-dependent (KI = 9150 microM, Kinact=0.048 min(-1)), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. CONCLUSIONS: Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part I: Phenobarbital, primidone, valproic acid, ethosuximide and mesuximide.

This article reviews 119 papers published since 1964 on the pharmacokinetics of phenobarbital, primidone, valproic acid, ethosuximide and mesuximide (methsuximide) in paediatric patients. Particular attention has been paid to the role of age in determining the variability of pharmacokinetic parameters, but the effect of other factors, such as different formulations and routes of administration, concomitant treatments, gender and pathological conditions other than epilepsy, have also been considered. Mean phenobarbital terminal half-life (t1/2z) is very long in neonates (45 to 409 hours) and decreases with age. Therefore, a low dose per kilogram (dose/kg) is recommended during the neonatal period. The dose requirement decreases with increasing age, especially in children also taking valproic acid, which inhibits phenobarbital metabolism. Primidone is metabolised to phenobarbital and phenylethylmalonilamide; the metabolic conversion rate is increased by enzyme-inducing drugs and inversely correlated with age, being virtually absent in neonates. Valproic acid is extensively bound to plasma proteins, but there is a high interindividual and intraindividual diurnal variability in the binding, which depends on the concentration of binding proteins (i.e. albumin) and binding modulators (e.g. free fatty acids) but not on age (at least in those patients aged between 3 months and 65 years). The clearance (CL/F) of valproic acid positively correlates with the unbound concentrations and is strongly age-dependent, being low in neonates and high at the end of the first postnatal month, and progressively decreasing from 2 months to 14 years. The combination of these factors leads to a very poor correlation between plasma concentrations and dose/kg (C/D) and between plasma concentrations of total valproic acid and efficacy. Children also taking enzyme-inducing antiepileptic drugs require a larger valproic acid dose/kg, whereas the coadministration of aspirin (acetylsalicylic acid) may decrease the clearance of unbound drug (CLu/F), and thus require a decrease in the daily dose of valproic acid. Ethosuximide is well absorbed, minimally protein bound and slowly eliminated. Lower C/D ratios are reported in children younger than 10 years old than in older children and in individuals also taking enzyme-inducing drugs (i.e. primidone). According to the only available paper on mesuximide in paediatric patients, the C/D ratio is less sensitive to both age and associated therapy.

Adolescent↗
PubMed1992

Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice: possible clinical significance.

Very young children with organic brain damage, intractable seizures, and developmental retardation are at particular risk of developing fatal hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mechanism of valproate-associated hepatic failure in these children is unclear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into poorly metabolized valproyl CoA and valproyl CoA metabolites. The other theory proposes that the unsaturated valproate derivative 2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates are toxic and directly cause irreversible inhibition of enzymes of beta-oxidation. The present study shows for the first time that in developing mice, when panthothenic acid and carnitine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the beta-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatment with carnitine alone was without effect. Findings support the CoA depletion mechanism of valproate inhibition of beta-oxidation and other CoA- and acetyl CoA-requiring enzymic reactions and stress the role of carnitine in the regulation of CoA synthesis at the site of action of pantothenate kinase.

Animals↗
PubMed1985

Improved direct injection method and extractive methylation method for determination of valproic acid in serum by gas chromatography.

Two simple methods for the determination of valproic acid in serum by gas chromatography are described. One is a direct injection method. To the serum sample are added an acetonitrile solution including an internal standard and hydrochloric acid. The sample is deproteinized and after centrifugation valproic acid in the supernatant is measured in the free form by direct injection into the gas chromatograph. The other is an extractive methylation method. To the serum sample are added an internal standard solution and a counter-ion solution, and the mixture is extracted into methylene chloride containing methyl iodide. Valproic acid is extracted into methylene chloride and simultaneously the methylation reaction proceeds. After centrifugation, an aliquot of the lower layer without evaporation is injected into the gas chromatograph. Both methods have been applied successfully to monitoring routine serum levels of valproic acid.

Chromatography, Gas↗
PubMedDate not supplied

An apparent fatal valproic acid poisoning.

While extensive data on therapeutic concentrations of valproic acid in plasma exist, data on toxic or fatal levels are very limited and superficial, interpretation of isolated blood levels obtained post-mortem is therefore a difficult task. A case of sudden death is described here. The circumstances are known and strongly indicate a fatal, suicidal poisoning by valproic acid at a dose of 56.4 g. Valproic acid was quantified in tissues by gas chromatography, and its identity confirmed by gas chromatography/mass spectrometry. The tissue concentrations found post-mortem were as follows: blood 720 mg/L; liver 800 mg/kg; stomach contents 1700 mg. Phenobarbitone and propoxyphene were also present at therapeutic concentrations. This data should provide a useful reference for interpretive purposes.

Adult↗