Pharmacokinetics valproic acid

Cloyd, J.C., Fischer, J.H., Kriel, R.L., and Kraus, D.M. (1993) Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 53 22-29. 

H. Salim, K. Badir, A. Haj Yeshia, M. Bialer, Pharmacokinetic Analysis of Ester Prodrugs of Valproic Acid , Pharm. Res. 1990, 7, S222. 

Herngren, L., Lundberg, B., and Nergardh, A. (1991) Pharmacokinetics of total and free valproic acid during monotherapy in infants. / Ne ro/ 238 315-319. 

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). 

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. 

Valproic acid, which is not an enzyme inducer, has no detectable effect on the pharmacokinetics of progestogens and estrogens (332). 

Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3 -azido-3 -deoxythymidine (ZDV) by human liver microsomes relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 1998 42(7) 1592-1596. 

Lertora JJ, Rege AB, Greenspan DL, et al. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 1994 56(3) 272-278. 

Booth CL, Pollack GM, Brouwer KL. Hepatobiliary disposition of valproic acid and valproate glucuronide use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions. Hepatology 1996 23(4) 771-780. 

There were no changes in lithium pharmacokinetics when risperidone was substituted open-label for another neuroleptic drug in 13 patients (634). On the other hand, an 81-year-old man had an acute dystonic reaction 4 days after lithium was added to a regimen of risperidone, valproic acid, and benzatropine (635). 

Conca A, Beraus W, Konig P, Waschgler R. A case of pharmacokinetic interference in comedication of clozapine and valproic acid. Pharmacopsychiatry 2000 33(6) 234—5. 

Note. For a review of the clinical pharmacokinetics of valproic acid see R. Gugler and G. E. von Unruh, Clin. Pharmacokinet.,... 

Rettenmeier, A. W., Gordon, W. R, Prickett, K. S., Levy, R. H., Baillie, T. A. Biotransformation and pharmacokinetics in the rhesus monkey of 2-n-propyl-4-pentenoic acid, a toxic metabolite of valproic acid. Drug Metab. Dispos. 1986, 14, 454-464. 

In this section we use a simulation study systematically to characterize the effect of noncompliance on steady-state pharmacokinetics. Specifically, the effect of missed and replacement doses on the steady-state pharmacokinetics of valproic acid (VPA) following the ER and DR preparations of the drug were investigated (31). 

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). 

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