Valproic Acid Clearance Research Articles

Predicted serum valproic acid concentrations in patients missing and replacing a dose of extended-release divalproex sodium

Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. Valproic acid concentration-time profiles were simulated for 1000 hypothetical patients for each of two missed-dose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extended-release divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. Simulation of two scenarios suggested that a missed dose of extended-release divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.

Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients.

This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.

Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.

Drug treatment of epilepsy in elderly people: focus on valproic Acid.

Despite old age being the commonest time of life to develop epilepsy, relatively little is known about the condition in later years. Antiepileptic drugs (AEDs) are the mainstay of treatment and valproic acid (VPA) has been prescribed for older patients with seizures for over 35 years. VPA is available in a variety of formulations. The drug is generally rapidly absorbed, although there are no data on the extent of oral absorption in the elderly. The volume of distribution (Vd) and elimination half-life have been compared in older and younger patients. One study reported no change in either parameter between elderly and younger patients (Vd: 0.16 vs 0.14 L/kg; elimination half-life: 15.3 vs 13.0h), the other found an increase in both for older patients (Vd: 0.19 vs 0.13 L/kg; elimination half-life 14.9 vs 7.2h). Total VPA clearance is similar in young and elderly subjects. The drug does not induce the metabolism of hepatic enzymes, but can act as a metabolic inhibitor, raising plasma concentrations of lamotrigine, phenobarbital (phenobarbitone), carbamazepine-10-11-epoxide, lorazepam, nimodipine and zidovudine. Concomitant use of VPA may also lead to an elevation in phenytoin, diazepam, warfarin, amitriptyline and chlorpromazine concentrations. A number of enzyme-inducing AEDs such as phenytoin, phenobarbital, primidone and carbamazepine can increase the clearance of VPA. Plasma concentrations of VPA may also rise when the drug is administered with felbamate, stiripentol, aspirin (acetylsalicylic acid), naproxen, phenylbutazone, isoniazid, fluoxetine and chlorpromazine. The majority of elderly patients present with partial and/or secondary generalised seizures, although a few have long-standing primary generalised seizures. Results from meta-analyses and randomised studies of patients comparing VPA with other AED monotherapies suggest that the drug is as effective as carbamazepine, phenytoin and phenobarbital in treating these seizure types. Although some of these studies recruited older patients, there have been no randomised double-blind trials examining the efficacy of VPA with other AEDs in an exclusively elderly cohort. There is no direct correlation between efficacy and plasma VPA concentrations. The majority of older patients require lower doses of AEDs than younger adults. Higher VPA doses may be needed in patients taking drugs which induce hepatic microsomal enzymes. Once-daily dosing of the controlled-release preparation can help to improve compliance and may render some frail elderly people seizure free. There is a perception that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults, although there are few data to validate this claim. Dose-dependent and idiosyncratic reactions may be more frequent. Common adverse effects of VPA include gastrointestinal symptoms and tremor. Slow-dose escalation and controlled-release preparations may minimise these. In summary, VPA is a long established AED. Its broad spectrum of action and dosing schedule are favourable properties for its use in older people. To accurately establish the place of this and other AEDs in treating elderly patients with epilepsy, well designed clinical trials are urgently required in this vulnerable population.

Effects of salicylate on the pharmacokinetics of valproic acid after oral administration of sodium valproate in rats

- Effects of salicylate on the pharmacokinetics of valproic acid (VPA) after oral administration (p.o.) of sodium valproate were investigated in rats. When salicylic acid was administered orally after sodium valproate p.o., the plasma VPA concentrations including maximum plasma concentration (C max ), area under the plasma concentration-time curve up to 3 h (AUC 0-3 ) and the elimination half-life ( t 1/2 ) of VPA were lower than control values. In addition, when salicylate was administered intraperitoneally or intravenously, the plasma VPA concentrations, AUC 0-3 and t 1/2 of VPA were lower than those in the control group. These results suggest that decreases in the plasma VPA concentrations including C max and AUC 0-3 with simultaneous oral administration of sodium valproate and salicylic acid may be related to both reduction of absorption and increase in clearance of VPA.

VALPROIC ACID HAS TEMPORAL VARIABILITY IN URINARY CLEARANCE OF METABOLITES

The reasons for the intra- and interindividual variability in the clearance of valproic acid (VPA) have not been completely characterized. The aim of this study was to examine day–night changes in the clearance of 3-oxo-valproate (3-oxo-VPA), 4-hydroxy-valproate (4-OH-VPA), and valproic acid glucuronides under steady state. Six diurnally active healthy male volunteers ingested 200 mg sodium valproate 12 hourly, at 0800 and 2000, for 28 days. On the last study day, two sequential 12-h urine samples were collected commencing at 2000 the evening before. Plasma samples were obtained at the end of each collection. Following alkaline hydrolysis, urine was analyzed for concentrations of VPA, 3-oxo-VPA, and 4-OH-VPA. A separate aliquot was assayed for creatinine (CR). The plasma concentrations of VPA, 3-oxo-VPA, 2-en-VPA, and CR were determined. The analysis of VPA and its metabolites was performed by GC–MS. There was an increase in plasma 3-oxo-VPA concentration at 0800, sampling as compared to 2000 sampling (p <. 05). The urinary excretion of 3-oxo-VPA and VPA glucuronides were decreased between 2000 and 0800, compared to between 0800, and 2000, by 40% and 50% respectively (p <. 05). These results indicate a nocturnal decrease in renal clearance of 3-oxo-VPA rather than a decrease in the β-oxidation of VPA at night. These differences were not explained by differences between the sampling periods in CR excretion. These results indicate the importance of collecting samples of 24-h duration when studying metabolic profiles of VPA. (Chronobiology International, 18(1), 123–129, 2001)

Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers.

The effects of coadministration of the non-steroidal anti-inflammatory drug diflunisal (DF) on glucuronidation and beta-oxidation of the antiepileptic agent valproic acid (VPA), and of VPA on DF glucuronidation, were studied in human volunteers. Seven healthy male volunteers received sodium valproate (NaVPA, 200 mg) orally twice daily for 7 days, after which all drug intake ceased for 1 month. The volunteers then took DF (250 mg) orally twice daily for 7 days. Both drugs were then taken (at the same doses as previously) twice daily for 7 days. On day 7 of each dosing phase, serial blood samples and all urine passed over the 12-h inter-dosing interval were collected. VPA, DF and selected metabolites were analysed using validated methods. Statistical comparisons of pharmacokinetic parameters were made using paired Student's t-tests. Mean plasma concentrations of total VPA were lower and apparent plasma clearances significantly higher during DF coadministration. This was associated with a significant 20% increase in the unbound fraction of VPA (from 6.6+/-1.3% to 7.9+/-1.8%). The apparent clearance of unbound VPA was not different. There was no evidence of any significant effect of DF coadministration on VPA metabolism: urinary recoveries of and formation clearances to urinary VPA-glucuronide, E-2-en-VPA, 3-oxo-VPA and 4-en-VPA were not significantly altered. However, there was a highly significant 35% increase in the area under the plasma concentration-time curve from 0-12 h (AUC0-12h) of 3-oxo-VPA and its renal clearance was lower, though not significantly so. VPA coadministration had no effect on DF pharmacokinetics or formation clearances of DF to its acyl glucuronide (DAG), phenolic glucuronide (DPG) or sulfate (DS) conjugates. However, plasma AUC0-12h values of the glucuronides were significantly lower and their renal clearances higher (though significantly so only in the case of DPG) during VPA coadministration. Steady-state coadministration of VPA and DF leads to a significant displacement of VPA from plasma protein binding sites. There was no evidence of competition for glucuronidation capacity or other metabolic interactions. Rather, the interactions detected appeared to be renal in nature, with renal clearance of 3-oxo-VPA being reduced by DF coadministration, and renal clearance of DPG and perhaps DAG being increased by VPA coadministration.

Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data.

The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one-compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: $¿rm Cl¿left (¿rm L/h ¿right )=0¿rm. 004¿times TBW¿times Dose ¿0.304¿¿rm ¿times 1.363¿,¿rm CBZ¿times 1. 541¿,¿rm PHT¿times 1.397¿,¿rm PB.$ The inter-individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter-individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter-individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately.

Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data

The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one-compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: (1) The inter-individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter-individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter-individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately. Copyright © 1999 John Wiley & Sons, Ltd.

Valproate population pharmacokinetics in children.

A population analysis of the kinetics of valproic acid (VPA) in children with epilepsy was performed in order to characterize the covariates which influence VPA clearance (CL). A total of 770 steady-state serum concentration samples was analysed. These were collected during VPA therapy from 255 children, aged 0.1-14 years and weighting 4-74 kg. Age, total body weight (TBW), VPA daily dose, sex and comedication with carbamazepine (CBZ) were considered as covariates. Population analysis was made with NONMEM program, assuming a one-compartment model, fixing the VPA absorption rate, bioavailability and distribution volume at values found in the literature. The results of the population pharmacokinetics analysis were validated in a group of 45 epileptic patients. The final regression model for VPA clearance, that included TBW (kg), daily dose (mg/kg) and CBZ comedication as covariates with a significant influence on this parameter, was as follows: CL (L/h) = 0.012 TBW0.715 DOSE0.306(1.359 CBZ). The coefficient of variation for interpatient variability in CL was 21.4% and the residual variability estimated was 23.9% for a concentration of 65 mg/l. In order to estimate the predictive performance of the selected final model, predictions of the VPA serum concentrations were calculated and compared with VPA measured concentrations in the validation group. This assessment revealed an important improvement in the predictive performance of VPA concentrations in comparison with the basic model that did not include any covariates (root squared mean error: 19.50 vs. 39.73 mg/l). A population pharmacokinetic model is proposed to estimate the individual CL for paediatric patients receiving VPA in terms of patient's dose, weight and concomitant CBZ, in order to establish a priori dosage regimens.

Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation.

This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism. In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions. Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it had been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate. Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of beta-oxidation. No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate's drug:drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.

Delayed Peak Serum Valproic Acid in Massive Divalproex Overdose—Treatment with Charcoal Hemoperfusion

Increased clearance and apparent clinical improvement in valproic acid overdose has been reported following in-series hemodialysis/hemoperfusion therapy. We report a case of divalproex sodium and chlorpheniramine overdose treated with charcoal hemoperfusion and multiple-dose activated charcoal. A 32-year-old female presented alert three hours postingestion of her own medication. Serum valproic acid was 105 micrograms/mL. No anticholinergic toxicity was seen. Despite three doses of activated charcoal over 14 hours, serum valproic acid continued to rise. Whole bowel irrigation and multiple-dose activated charcoal were commenced 17 h postingestion when serum valproic acid was 1380 micrograms/mL. Charcoal hemoperfusion was instituted three hours later when serum valproic acid had not fallen and the patient remained obtunded. Initial extraction ratio of the hemoperfusion cartridge was 0.54 with plasma clearance of 54.5 mL/min. Valproic acid elimination half-life was 3 h during the 190 min hemoperfusion cycle. Posthemoperfusion elimination half-life was 4.8 h with continued multiple-dose activated charcoal dosing. The clinical condition improved during hemoperfusion. Enteric coated valproic acid preparations may cause delayed toxicity in overdose, particularly with coingested anticholinergic medications. In our case, charcoal hemoperfusion appeared to increase valproic acid clearance.

Clinical Pharmacokinetics of Antiepileptic Drugs in Paediatric Patients

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.

Age-dependent intestinal absorption of valproic acid in the rat.

The absorption of valproic acid (VPA) across isolated perfused segments of jejunum, ileum and colon was examined in situ in 14-day- to 24-month-old Fischer-344 rats. Within each age group, the intrinsic absorptive clearance (Cla) of VPA at a perfusate concentration of 1 mg/ml was highest in the jejunum, lowest in the colon, and intermediate in the ileum. When intestinal Cla was normalized for the dry weight of the segment, within-group variability decreased. In all segments, VPA Cla normalized by dry weight decreased during development (< or = 20 to 90 days) and remained relatively constant during aging (90 days to 24 months). The mechanism of valproate absorption (active vs. passive) was examined across age in everted intestinal sacs prepared from each of the three segments. Data were consistent with active transport of VPA in the jejunum and ileum of rats of all ages, and in the colon of pre-weanling animals. Colonic absorption of VPA appeared to occur by passive diffusion in adult rats. In contrast, colonic absorption of d-glucose occurred, only by passive diffusion in all age groups. These data indicate that, during development, significant alterations in the rate of VPA absorption occur throughout the rat intestine. Furthermore, while active transport of VPA by the small intestine was present throughout the age range investigated, active transport by the colon became negligible by the time of weaning.

The effect of felbamate on valproic acid disposition

Felbamate is a new antiepileptic drug approved for partial and secondarily generalized seizures. Subjects with epilepsy (three men and seven women; age range, 20 to 39 years; weight range, 53 to 88 kg) who were previously stabilized with valproic acid, 9.5 to 31.7 mg/kg/day, received both 600 and 1200 mg felbamate twice a day in an open-label, randomized, crossover study. Coadministration of 1200 or 2400 mg felbamate increased the mean valproic acid area under the curve (from 802.2 to 1025.4 and 1235.9 mg/hr/ml, respectively), peak concentrations (from 86.1 to 115.1 and 133.4 mg/ml, respectively), and average steady-state concentrations (from 66.9 to 85.5 and 103.0 mg/ml, respectively). No changes were observed in valproic acid time to peak concentration or protein binding. Average steady-state felbamate concentrations were 34.7 mg/ml for 600 mg administered twice daily and 61.2 mg/ml for 1200 mg administered twice daily. When felbamate is added to a regimen of valproic acid, valproic acid doses may require reduction because coadministration of felbamate decreased steady-state valproic acid clearance (28% and 54%, respectively; p < 0.01).

Clearance of valproic acid from cerebrospinal fluid in anesthetized rabbit.

Clearance of valproic acid from brain tissue is believed to occur via a carrier-mediated system(s). The present study was designed to determine whether clearance was capacity-limited (saturable) and whether it occurred primarily at the choroid plexus. Ten rabbits were anesthetized with halothane and surgically prepared for ventriculocisternal perfusion. In group 1 (n = 5) valproic acid was added to blue dextran-containing mock cerebrospinal fluid (CSF) to achieve concentrations of 5, 20, 100, and 500 micrograms.ml-1. The mixture was infused through needles in both cerebral ventricles. The purpose of this group was to determine whether over a large range (100x) of valproic acid concentrations, clearance from CSF was capacity limited (saturable). In group 2 (n = 5) valproic acid concentrations were 3, 10, and 30 microgram.ml-1 and infusion was into the left cerebral ventricle only. The purposes of this group were to determine (a) the magnitude of valproic acid clearance for the "clinical" range of valproic acid in CSF (10-30 micrograms.ml-1), and (b) whether clearance of valproic acid was changed by perfusion across a portion of the choroid plexus surface area (group 2) as compared with perfusion across the entire choroid plexus surface area (group 1). In both groups the percent extraction of valproic acid was calculated from the concentration ratio (valproic acid)out/(valproic acid)in corrected for the rate of CSF formation. In group 1 the percent extraction of valproic acid was 93 +/- 2% (mean +/- SD) at 5 micrograms.ml-1 and stabilized within the range of 58-70% (individual values) at the higher inflow concentrations of valproic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonlinear elimination and hepatic concentration of conjugation‐ metabolite of valproate in guinea‐pigs

The plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea-pigs placed on various (0.08-9 mumol ml-1 = 11-1303 micrograms ml-1) steady-state plasma concentrations (Css) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 mumol ml-1 (88 micrograms ml-1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (Vmax) and the Michaelis-Menten constant (Km) for the primary (Vmax1, Km1) and the secondary (Vmax2, Km2) pathways were Vmax1 = 1.52 mumol min-1 kg-1, Km1 = 0.15 mumol ml-1, Vmax2 = 24.98 mumol min-1 kg-1 and Km2 = 11.70 mumol ml-1, respectively. The Km1 value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose-dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (fu), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The Km value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the Km1 value.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic and metabolic influences on enterohepatic recirculation: Simulations based upon the disposition of valproic acid in the rat

The potential influence of alterations in several physiologic processes (hepatocellular egress, biliary excretion, gastrointestinal transit) and biotransformation steps (oxidative metabolism, glucuronidation) on the disposition of agents subject to significant enterohepatic recirculation (ER) via the glucuronide conjugate was examined in a series of simulation experiments. The model of ER developed was based upon the disposition of valproic acid (VPA) and valproate glucuronide (VPA-G) in the rat. The systemic disposition of VPA was simulated following changes in several processes contributing to (or competing with) ER: hepatic oxidative metabolism, hepatic glucuronidation, sinusoidal egress of glucuronide conjugate, canalicular egress of glucuronide conjugate, and gastrointestinal transit. Changes in the formation clearance of VPA-G resulted in a less than proportional change in systemic clearance of VPA, whereas changes in oxidative metabolism led to a greater than proportional change in systemic clearance. Furthermore, alterations in hepatocellular egress of VPA-G affected the disposition of the parent compound, suggesting that drug interactions or disease state effects on metabolite transport may be misinterpreted as effects at the level of metabolite formation. Analytical methods are proposed to recover the intrinsic kinetic parameters (formation clearances of metabolites, renal clearance of parent, volume of distribution) in the presence of ER from the systemic disposition of the parent alone.

The effect of hemodialysis and hemoperfusion on serum valproic acid concentration

We report a patient with dialysis-induced encephalopathy who was taking divalproex sodium for a seizure disorder. Her serum valproic acid concentration appeared to be in the low therapeutic range at 54 mg/l yet she continued to have seizure activity. The elimination half-life and apparent clearance of valproic acid were the same for both a dialysis and nondialysis day, indicating that hemodialysis/hemoperfusion has little effect on the overall removal of valproic acid from the body.

The effect of carbamazepine on valproic acid disposition in adult volunteers.

1. Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg-1 day-1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2. After CBZ administration, mean VPA plasma clearance increased from 0.90 +/- 0.18 s.d. to 1.26 +/- 0.24 l h-1 (P less than 0.05) as did clearance of free VPA (20.8 +/- 7.6 to 37.0 +/- 13.6 l h-1). Mean VPA elimination rate constant increased from 0.051 +/- 0.011 to 0.067 +/- 0.011 h-1 (P less than 0.05) after CBZ administration. 3. Mean area under the serum concentration vs time curve decreased from 675.0 +/- 130.5 to 475.7 +/- 75.7 mg l-1 h (P less than 0.05) after CBZ administration. Mean serum VPA half-life decreased from 14.0 +/- 2.4 to 10.6 +/- 1.4 h (P less than 0.05). Mean serum VPA trough concentrations decreased from 44.0 +/- 16.7 to 27.0 +/- 10.4 micrograms ml-1 (P less than 0.05). 4. A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5. Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.