Valproic acid half-life

Valproic acid/ Modulate sodium Loading dose Half-life 50-100 mcg/mL Drowsiness, nausea, Hepatotoxicity,... 

Half-life (t1/2) 18-27 hours (adult) greater than 36 hours (elderly or patients with renal impairment) Cytochrome P-450 (CYP450) isoenzyme t1/2 decreases over time due to autoinduction 25-65 hours (initial) 12-1 7 hours (adult multiple dosing) 8-14 hours (children multiple dosing) 2 hours (parent) 9 hours (metabolite) 5-20 hours (adult) 25 hours increases to 59 hours with concomitant valproic acid therapy... 

The main rout of excretion of the drug and its metabolites is the kidney with a half-life of 9-18 h in human. In contrast to human, animal models have a lower elimination half-life ranging from 0.6-9 h [78]. The elimination half-life of valproic acid and some metabolites was found to be much longer in the neonates (40-50 h) than adult subjects (9-18 h) [78,81]. One study reported no difference between the elimination half-life between elderly and young subjects (15.4 and 13.0 h, respectively) while other found an increase in for older patients (14.9 versus 7.2 h for young patients) [78,90], Insignificant amounts of valproic acid are found in breast milk, approximately 3% of maternal drug levels [84]. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

The distribution of DVP appears to be restricted to plasma and rapidly exchangeable extracellular water (AHFS, 2000). The volume of distribution is 0.26 L/kg in children and 0.19 L/kg in adults (AHFS, 2000). The half-life is 7.2 2.3 hours in children and 13.9 3.4 hours in (healthy) adults (Levy et al., 1984). Valproic acid has been detected in CSF (approximately 10% of serum concentrations) and milk (about 1%-10% of plasma concentrations). The drug crosses the placenta. Valproic acid may displace other drugs from proteinbinding sites. 

Valproic acid is eliminated by first-order kinetics and has an elimination half-life of 5-20 hours (average, 10.6 hours). Pediatric patients (3 months to 10 years) have a 50% higher clearance of the drug expressed by weight (i.e., mL/min/kg) over the age of 10 years, pharmacokinetic parameters of valproic acid approximate those in adults (Cloyd et al., 1993). Valproic acid is metabolized principally in the liver by (3 (over 40%) and CO oxidation (up to 15%-20%). Thirty through 50% of an administered dose is excreted as glucuron-ide conjugates (Cloyd et al., 1993). 

Several valproate preparations are available in the United States, including valproic acid, sodium valproate, divalproex sodium, and an extended-release preparation of divalproex sodium. Divalproex sodium is a dimer of sodium valproate and valproic acid with an enteric coating, and it is much better tolerated than other oral valproate preparations. An intravenous preparation also has become available, but it has not been well studied in patients with psychiatric disorders. The half-life of valproate is 9-16 hours. 

Felbamate appears to have multiple mechanisms of action. It produces a use-dependent block of the NMDA receptor, with selectivity for the NR1-2B sub-type. It also potentiates GABAa receptor responses. Felbamate has a half-life of 20 hours (somewhat shorter when administered with either phenytoin or carbamazepine) and is metabolized by hydroxylation and conjugation a significant percentage of the drug is excreted unchanged in the urine. When added to treatment with other antiseizure drugs, felbamate increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine. 

Less than 3% of a dose is excreted unchanged in the urine or through the feces. The elimination half-life from plasma is 10-15 h when valproic acid is used alone, but interaction with other anticonvulsant drugs can reduce the half-life to 4-10 h. It may be much longer in hepatic-impaired individuals, the elderly, and young children. 

Valproic acid is rapidly and almost completely absorbed after oral administration. Peak concentrations occur 1 to 4 hours after an oral dose. The principal metabolite, 2-n-propyl-3-ketopentanoic acid, is created by action of CyP 2C19 and has anticonvulsant activity comparable to that of valproic acid, although this metabolite does not accumulate in plasma the exact cytochrome enzyme isomer involved in metabohsm has not been identified. The single-dose half-life is 16 hours in healthy adults, but this decreases to 12 hours on chronic therapy and may be as short as 8 hours in children. In neonates and in hepatic disease, when metabolism is reduced, the half-life becomes prolonged. Valproic acid is highly protein bound (93%). In circumstances when competition for protein binding increases, such as in uremia, cirrhosis, or concurrent drug therapy, the percent of free valproic acid increases. 

Tiagabine has an elimination half-Ufe of 7 to 9 hours. In patients receiving CyP 3A4 inducing anti-epileptic drugs (AEDs), the elimination half-life decreases to 4 to 7 hours. Phenytoin, phenobarbital, and carbamazepine are CyP 3A4 inducers. Valproic acid and gabapentin are not. Tiagabine is not considered to be a CyP 3A4 inducer. ... 

Drug Interactions. Enzyme inducers, such as carbamazepine and phenytoin, increase tiagabine clearance and decrease the half-life. Food decreases the rate but not the extent of absorption. Tiagabine is displaced from protein by naproxen, salicylates, and valproate. However, tiagabine does not displace phenytoin, valproic acid, amitrypty-line, tolbutamide, or warfarin. ... 

Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and potential toxicity if the dose of phenobarbital is not reduced. Valproic acid may increase concentrations of 10,11-carbamazepine epoxide without affecting concentrations of the parent drug via inhibition of epoxide hydrolase. Valproic acid is also a potent inhibitor of lamotrigine, via inhibition of UGT enzymes, and can result in a doubling of the half-life of lamotrigine. ... 

Pharmacokinetics. Lamotrigine is rapidly and completed absorbed (with little first-pass metabolism), has 55% protein binding, is metabolized predominantly by hepatic glucuronic acid conjugation, and is renally excreted. " The normal half-life is approximately 25 hours with concomitant valproic acid it increases to 59 hours, and with carbamazepine it decreases to 15 hours (see Table 68-11). ... 

Chlorpromazine, cimetidine, and salicylates decrease the clearance of valproic acid and increase its half-life. Addition of valproic acid to phenobarbital may result in an increased phenobarbital level and an increase in CNS effects. 

The simplest HDAC inhibitors are short chain carboxylic acids such as butyric acid, where presumably the acid is the zinc-binding group. These are relatively low in potency (micromolar IC50). Valproic acid, an old drug used as an anticonvulsant, is similarly a modest H DAC inhibitor and has now advanced to clinical trials as an anticancer agent (Fig. 12-5). The low potency, combined with short half-life and metabolic instability are the liabilities associated with this class of HDAC inhibitors. 

Could the half-life of valproic acid be altered in a patient with chronic obstructive pulmonary disease (COPD) ... 

Valproic acid significantly decreases the clearance of lamotrigine, due to competition for hepatic glucuronidases. Elimination half-life is more than doubled if valproate is administered concurrently. 

Hicks LK, McFarlane PA Valproic acid overdose and haemodialysis. Nephrol Dial Transplant 2001 16(7) 1483-1486. [PMID 11427646] (Case report with peak VPA level 998 mg/L had reduction in half-life from 23.5 h to 2.25 h with hemodialysis. Includes review of the literature.)... 

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