Valproic acid absorption

Class I compounds have both good solubility and permeability and generally offer no problems with regard to having a good absorption profile (e.g., acetaminophen, disopyramide, ketoprofen, metoprolol, nonsteroidal anti-inflammatory agents, valproic acid, verapamil). In general, one would not expect the presence of food to influence the absorption of this class... 

The infrared absorption spectrum of sodium valproate and valproic acid were obtained in a KBr disc using a Perkin-Elmer infrared spectrophotometer. The infrared spectra of sodium valproate and valproic acid are shown in Figs. 4A and... 

B, respectively. The infrared absorption bands assignments for sodium valproate and valproic acids are shown in Table 2(A) and (B), respectively. 

Fig. 4. (A) The infrared absorption spectrum of sodium valproate obtained in a KBr pellet. (B) The infrared absorption spectrum of valproic acid obtained in a KBr pellet.

Examine the test article by infrared absorption spectrophotometry, and compare with the spectrum obtained with a valproic acid reference standard [10,11]. 

Lee et al. [30] described a micellar electrokinetic capillary chromatographic method for the determination of some antiepileptics including valproic acid. They used a fused silica capillary column (72 cm x 50 pm) and SDS as the micellar phase and multiwavelength UV detection. Reaction conditions, such as pH and concentration of running buffer were optimized. Solutes were identified by characterizing the sample peak in terms of retention time and absorption spectra. Recoveries were 93-105%. 

The absorption, excretion, and biotransformation of valproic acid were studied by Kukino and Matsumoto (14). 

Absorption - /a pro c acid is rapidly and almost completely absorbed from the Gl tract. Absorption of the drug is delayed but not decreased by administration with meals administration of the drug with milk products does not affect the rate or degree of absorption. The bioavailability of valproate from divalproex sodium delayed-release tablets and capsules containing coated particles has been shown to be equivalent to that of valproic acid capsules. 

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. 

An understanding of absorption, binding, metabolism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, triiodothyronine, valproic acid, sulfafurazole, and salicylic acid. 

The antiseizure drugs exhibit many similar pharmacokinetic properties—even those whose structural and chemical properties are quite diverse— because most have been selected for oral activity and all must enter the central nervous system. Although many of these compounds are only slightly soluble, absorption is usually good, with 80-100% of the dose reaching the circulation. Most antiseizure drugs (other than phenytoin and valproic acid) are not highly bound to plasma proteins. 

The monocarboxylic acid transporter family MCT (mostly MCT1) was investigated in the past decade for its involvement in intestinal, nondiffusional drug absorption. Typical studies have indicated that salicylic acid [150], tolbutamide [151], atorvastatin (a water-soluble derivative of coenzyme A) [152], and valproic acid [153] are probably uptaken, at least in part, by MCT into the bloodstream. 

PLATINUM COMPOUNDS ANTIEPILEPTICS -CARBAMAZEPINE, PHENYTOIN, VALPROIC ACID l plasma concentrations of antiepileptic, which t risk of seizures Due to impaired absorption of antiepileptic Monitor closely for seizure activity and warn patients and carers. Need to adjust dosage using parameters such as blood levels to ensure therapeutic levels... 

Co-administration of acetazolamide with primidone results in decreased gastrointestinal absorption of primidone and subsequent diminished plasma concentrations. Primidone administered in association with phenytoin produces a modest elevation of the phenobarbital/primidone ratio because phenytoin competes with the hepatic hydroxylating enzymes associated with phenobarbitaFs metabolism. Coadministration of valproic acid, for the same reasons out-fined for phenobarbital, causes a modest increase in both primidone and phenobarbital serum concentrations. 

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. ... 

Pharmacokinetics. Valproic acid appears to be absorbed completely from available oral dosage forms when administered on an empty stomach. However, the rate of absorption differs among preparations. Peak concentrations occur in 0.5 to 1 hour with the syrup, 1 to 3 hours with the capsule, and 2 to 6 hours with the enteric-coated tablet. The extended-release formulation (Depakote-ER) is FDA approved for use in both patients with migraine headache and epilepsy. It should be noted, however, that the bioavailability of this formulation is approximately 15% less than that of enteric-coated divalproex sodium (Depakote). 

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. ... 

Describe the absorption of valproic acid and sodium valproate. 

What effect would concurrent administration of antacids have on the absorption of valproic acid ... 

Because valproic acid is well absorbed in the acid milieu of the stomach, the ingestion of antacids, H2 receptor blockers, or proton pump inhibitors decreases the absorption of the drug. 

There is an increased risk of diarrhea in patients taking misoprostol with the m nesium-containing antacids. Sulfasalazine may increase the risk of toxicity of oral hypoglycemic dru, zidovudine, methotrexate, and phenytoin. There is an increased risk of crys-talluria when sulfasalazine is administered with medienamine. A decrease in the absorption of iron and folic acid may occur when these ents are administered with sulfasalazine. When bismuth subsalicylate is administered witli aspirin-containing dru, there is an increased risk of salicylate toxicity. There is an increased risk of toxicity of valproic acid and methotrexate and decreased effectiven s of the corticosteroids when these agents are administered with bismuth subsalicylate. 

Colesevelam appears to be less likely to interfere with the absorption of concurrently administered drugs. No significant decreases in absorption were seen when colesevelam was coadministered with either digoxin, lovastatin, warfarin, metoprolol, quinidine, or valproic acid. Because of potential interactions, especially for drugs with a low therapeutic index, the administration of drugs that have not been directly studied in combination with colesevelam should be spaced accordingly, as described above tor cholestryamine and colestipol (7,15). 

Valproic acid is rapidly and completely absorbed from the gastrointestinal tract. There is a delay in the absorption with the preparation Depakote (divalproex sodium), because of its delayed-release fonaulation as well as the intestinal conversion of divalproex to 2 molecules of valproic acid. 

A. Specific levels. Obtain a stat serum valproic acid level. Serial valproic acid level determinations should be obtained, particularly after ingestion of divalproex-containing preparations (Depakote), owing to the potential for delayed absorption. Peak levels have been reported up to 18 hours after Depakote overdose, and could be even later after ingestion of the new formulation Depakote ER. 

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