Valproic acid, metabolites

Tong, V., X. W. Tong, T. K. Chang, and E. S. Abbott. 2005. Valproic acid. I. Time course of lipid peroxidation markers, liver toxicity and valproic acid metabolites in rats. Toxicological Science 86 427 35. 

It has been proposed that hepatotoxicity is a consequence of the further biotransformation of the valproic acid metabolite 2-propyl-4-pentenoic acid (also called VPA). ... 

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... 

Nuclear magnetic resonance spectroscopy was investigated as a method to screen for organic substances (and metabolites) in patients with indications of a drug overdose [17]. Urine specimens containing valproic acid were examined by H-NMR spectroscopy at 300 MHz and the results compared with GC MS. 

Negative ion Cl-MS The method determined and identified valproic acid and 15 of its metabolites [73]... 

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]. 

The answer is d. (Katzung, pp 411, 1029.) An increased incidence of spina bifida may occur with the use of valproic acid during pregnancy Cardiovascular, orofacial, and digital abnormalities may also occur. The main issue with the use of phenobarbital or primidone (metabolite is phe-nobarbital) for the fetus is neonatal dependence on barbiturates. 

Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations ofthe 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant. 

At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-ene-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. At least 67 cases of hepatotoxicity have been reported, and most deaths were in mentally retarded children less than 2 years old who were receiving multiple drug therapy. 

Determination of Valproic Acid and Its Metabolites in Biological Fluids... 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

Tang, W. and Abbott, F.S. 1996. Characterization of thiol-conjugated metabolites of 2-propylpent-4-enoic acid (4-ene VPA), a toxic metabolite of valproic acid, by electrospray tandem mass spectrometry. J. Mass Spectrom. 31 926. 

W. Loscher, H. Nau, Pharmacological Evaluation of Various Metabolites and Analogues of Valproic Acid , Neuropharmacology 1985, 24, 427-435. 

There is an informative parallel to be drawn between the metabolism of fatty acids and that of valproic acid (VA), a well-known anti-epileptic drug. One of the metabolites of VA is A4-valproic acid (10.54, Fig. 10.16), which undergoes a number of metabolic transformations, including oxygenation to epoxide 10.55. Rather than being a substrate for EH, this epoxide reacts by intramolecular nucleophilic attack of the carboxylate anion at the internal C-... 

Fig. 10.16. Comparison of the metabolism of A4-valproic acid (10.54), a metabolite of valproic acid, with that of ethyl A4-valproate (10.57), a synthetic analogue. Both compounds undergo cytochrome P450 catalyzed oxygenation to form the corresponding epoxides (10.55 and 10.58, respectively). The former reacts intramolecularly to form the lactone 10.56 and is not detectably a substrate for epoxide hydrolase. Epoxide 10.58, in contrast, is a substrate for epoxide hydrolase, forming the diol 10.59, which, in turn, carries out an intramolecular nucleophilic attack to form lactone 10.56 [136],...

Drug/Lab fesf/nferacf/ons Valproic acid is partially eliminated in the urine as a keto-metabolite, which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproic acid. 

Flurazepam (Dalmane) [C-IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose Adults Beds >15 y. 15-30 mg PO qhs PRN X in elderly Caution [X, /-] Elderly, low albumin, hepatic impair Contra NAG PRG Disp Caps SE Hangover d/t accumulation of metabolites, apnea, anaphylaxis, angioedema, amnesia Interactions T CNS depression W/ antidepressants, antihistamines, opioids, EtOH T effects OF digoxin, phenytoin T effects W/ cimetidine, disulfiram, fluoxetine, iso-niazid, ketoconazole, metoprolol, OCPs, propranolol, SSRIs, valproic acid. 

Nau, H. and Loscher, W. (1984) Valproic acid and metabolites pharmacological and toxicologic studies. Epilepsia 25(Suppl 1) S14-S22. 

Valproic acid is a potent inhibitor of histone deacetylase and through this mechanism changes the transcription of many genes. A similar effect, but to a lesser degree, is shown by some other antiseizure drugs (topiramate, carbamazepine, and a metabolite of levetiracetam). 

Propylpentanoic acid (valproic acid) (12) contains no chiral centers, but one of its mammalian metabolites is 2-propyl-4-pentenoic add (14), which has a chiral center at C-2. (S)-2-Propyl-4-pentenoic acid is a much more potent teratogen, at least in some assays, than (R)-2-propyl-4-pentenoic acid [56]. Similar observations have been made for the specific enantiomers of 2-propyl-4-pentynoic acid (15). (S)-2-Propyl-4-penty-noic acid is a much more potent teratogen than (R)-2-propyl-4-pentynoic acid [57]. 

Isosteric substitution of the C-2 hydrogen atom of valproic acid (12) with a fluorine atom affords 2-fluorovalproic acid (22), which causes significantly less hepatoxicity than valproic acid, although a reduction in anticonvulsant properties is also observed [59, 60]. The hepatoxicity of 12 involves hepatic cytochrome P450-mediated metabolism to its 4-ene metabolite (14), which undergoes further metabolism, specifically mitchondrial (3-oxidation, to provide ( )-2-propyl-2,4-pentadienoic add (23), a reactive electrophilic metabolite [59, 60]. 

Figure4.4 Structures of valproic acid (12), its 4-ene metabolite (14), its 2,4-diene metabolite (23), and 2-fluorovalproic acid (22). Compound 23 is believed to be responsible for the...

Hauck, R.-S. and Nau, H. (1996) Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-ene-VPA), an active metabolite of the anticonvulsant drug, valproic acid. Toxicol. Lett. 49 41-48. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

The two most serious toxic effects of valproic acid are hepatocellular injury (96) and teratogenesis (97). Since CYP2A6 and CYP2C9 are known to oxidize valproic acid to a 4-ene metabolite that is hepatotoxic, inducers of these isoforms, including other antiepileptic agents, are likely to increase the risk of hepatotoxicity (98). However, valproic acid also is metabolized by several other pathways that may be involved in causing its toxicities (99). 

Porubek DJ, Grillo MP, Olsen RK, et al. Toxic metabolites of valproic acid inhibition of rat liver acetoacetyl-CoA thiolase by 2-n-propyl-4-pentenoic acid (A4-VP A) and related branched chain carboxylic acids. In Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanisms of Toxicity. New York Raven Press, 1991 53-58. 

Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit 1999 21(3) 341-5. 

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