Antiepileptic drug metabolism

Dam M, Christiansen J, Munck O, Mygind KI. Antiepileptic drugs Metabolism in pregnancy. Clin Pharmacokin 1979 4 53-62. 

Inhibitors of Cytochrome P-450 (CYP) Isozymes and UDP Glucuronosyltranferase (UGT) Involved in Antiepileptic Drug Metabolism... 

Enzymic oxidations at the 7-position of pyrido[2,3-oxygenated derivatives and of the 8-N-oxide have been observed in the metabolism of the pyrido[2,3-e/]pyrimidine analogues of the antiepileptic drug methaqualone (75MI21502, 74MI21500). 

Drug Interactions Carbamazepine induces the hepatic metabolism of many drugs, including other antiepileptic drugs, antipsychotics, some antidepressants, oral contraceptives, and... 

Valproic acid and its salts are a new group of antiepileptic drugs that differs from the known drugs both structurally and in terms of its mechanism of action. It is believed that it acts on the metabolism of the GABA system. Valproic acid has been shown to elevate the level of GABA in the brain by means of competitive inhibition of GABA transaminase and the dehydrogenase of succinic semialdehyde. 

Metaboiism/Excretion- Primarily metabolized in liver. Mean terminal half-life for valproate monotherapy ranges from 9 to 16 hours. Half-lives in the lower part of the range usually are found in patients taking other enzyme-inducing antiepileptic drugs. 

There are some clinically important pharmacodynamic drug-drug interactions to be mentioned. Antipsychotics will potentiate the central depressant effects of sedatives and of alcohol. They will also increase the risk of respiratory-depressant effects of opiates. Inducers of drug metabolic enzymes like for example rifampicin and several antiepileptics, may increase the elimination rate of antipsychotic agents and thus decrease their efficacy. 

Methylphenidate is an inhibitor of drug metabolizing enzymes of the cytochrome P450 family and several interactions with drugs like some antiepileptics, antidepressants and oral anticoagulants, have been described. 

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. 

A review of HPLC methods for antiepileptic drug analysis was published in 1987 by Juergens.18 Standard analytical separations were compared with narrow-bore separations, and a 70% reduction in the cost of solvents was possible, owing to a reduction in flow rate from 1 ml/min for the analytical column to 0.3 ml/min for the narrow-bore column. Gayden et al.19 developed an isocratic method, using narrow-bore columns, to quantify adenosine (Ado) release by dispersed rat renal outer medullary cells under conditions of normoxia and hypoxia. Standard HPLC with UV detection has been the predominant method for studying the metabolic pathways of adenosine and measuring the Ado breakdown products inosine (Ino) and hypoxanthine (Hyp). However, the conventional methods lack reliability... 

Argikar U. Effects of age, induction, regulation and polymorphisms on the metabolism of antiepileptic drugs. In PhD. thesis. Minneapolis University of Minnesota, 2006. 

Valsamis HA, Arora SK, Labban B, et al. Antiepileptic drugs and bone metabolism. Nutr Metab (Lond) 2006 3 36. 

Absorption and metabolism Carbamazepine is absorbed slowly following oral administration. It enters the brain rapidly because of its high lipid solubility. Carbamazepine induces the drug metabolizing enzymes in the liver, and its half-life therefore decreases with chronic administration. The enhanced hepatic P-450 system activity also increases the metabolism of other antiepileptic drugs. 

Several metabolic interactions between clobazam and other antiepileptic drugs have been reported, in particular phenytoin intoxication after the addition of clobazam (SED-12, 98). 

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