Valproic acid distribution

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Sodium valproate is converted to valproic acid in the intestine and the acid is absorbed. Absorption may be delayed by food or by enteric-coated tablets. Valproic acid has a low volume of distribution and high plasma protein binding. In the elderly there is a risk for increased free valproic acid concentrations requiring lower doses and plasma concentrations at the lower therapeutic range. However it should be realized that these plasma concentrations do not correlate very well with the therapeutic or toxic effects and careful observation for symptoms is mandatory. 

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. 

Keen CL, Peters JM, Hurley LS (1989) The effect of valproic acid on e5Zn distribution in the pregnant rat. J Nutr, 119 607-611. 

Valproic acid is 90% bound to plasma proteins, although the fraction bound is somewhat reduced at blood levels greater than 150 uglmL. Since valproate is both highly ionized and highly protein-bound, its distribution is essentially confined to extracellular water, with a volume of distribution of approximately 0.15 L/kg. 

Renal disease (uraemia) may increase the volume of distribution of acidic drugs that extensively bind to plasma albumin (e.g., phenytoin, valproic acid, naproxen, phenylbutazone, furosemide). As decreased protein binding would increase the unbound (free) fraction in the plasma, the therapeutic concentration range (based on total drug concentration) would be lower than the usual... 

Valproic acid is rapidly distributed and the plasma protein binding is concentration dependent (18). As previously noted, valproic acid is extensively metabolized, primarily in the liver, with about 30-50% of the drug excreted as the glucuronide (phase II metabolism) in the urine, about 30-40%by the phase I mitochondrial j3-oxidation pathway, and about 10-20% by microsomal cytochrome P450-mediated hy droxylation/dehydrogena-tion of the side chain that provides the major phase I metabolites (36). The metabolites of valproic acid have been thought to be the cause of a rare, but fatal hepatotoxicity (35). The synthetic ( )-2,4-diene VPA has been shown to induce the same hepatic microve-sicular steatosis seen in patients, in chronic administration studies in rats (36). The ultimate causative factor (s) of hepatoxicity of valproic acid currently remain undefined (28,29). 

Each simulation included 100 hypothetical subjects. The model parameters used were derived from an adult population and there were no covariate distribution models for the virtual trial population. Subjects were assumed to be healthy and on valproate monotherapy (31). The simulations assumed that the extended release (ER) formulation was administered once daily and the delayed release (DR) preparation was administered twice daily. Unbound and total valproic acid concentrations were simulated from the time of dose administration to 280 h and the simulations were based on the administration of 1000 mg ER once daily, 500 mg DR twice daily, 2500 mg ER once daily, and 1000 mg DR twice daily. For once-daily regimens, simulation scenarios included doses taken 6, 12, 18, and 24h late from schedule and then two doses taken 24h late (replacement dose for the missed dose). For the twice-daily regimens, doses were simulated 3,6,9, and 12 h later than the scheduled times and then two doses were simulated 12 h later than scheduled to mimic replacement dosing for a missed dose. More extreme cases where two doses are delayed at various times or missed were also simulated. 

I Pharmacokinetics. Valproate sodium is rapidly converted to valproic acid in the stomach, whereas divalproex sodium delayed-release and extended-release tablets must pass into the small intestine to be converted to valproic acid. Valproic acid is highly bound to albumin and other plasma proteins, and it is extensively metabolized in the liver. A summary of the absorption, distribution, metabolism, and elimination data for valproate is found in Table 68-11. ... 

Dickinson, R.G. et al., Disposition of valproic acid in the rat Dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect, J. Pharmacol. Exp. 

It is known that both the metabolism and the biological effects of 2-APA drugs can be modulated by other xenobiotics that influence the pool of free CoA or the activity of the CoA-dependent enzymes. Clofibrate and possibly other clofibric acid derivatives can increase the expression of long-chain acyl-CoA synthase and increase ibuprofen incorporation and tissue distribution into hybrid lipids in rats and humans [27,56-59]. The addition of valproic acid and pivalic acid, a metabolite of pivampicillin, to suspensions of isolated rat hepatocytes can also interfere with CoA pools and inhibit the formation of ibuprofenoyl-CoA reaction [60,61]. 

In an open label, two-way crossover study, healthy volunteers were orally administered 1.2 g of a powdered extract of Chinese peony daily for 7 days prior to oral administration of 200 mg valproic acid. An increase in the absorption rate of valproic acid in the treatment group was observed as compared to control, but no significant effects on distribution, metabolism, or elimination were observed (Chen et al. 2000). 

Within the CNS class only 27 compounds had a single acid. While this is a low number, the distribution of pKa values was nonetheless very interesting. Figure 3 shows that the majority of acids had a pKa above 7 and only one fell below 6.1 (valproic acid = 4.8). 

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