Interaction between valproate and branched-chain amino acid metabolism.
Structural similarities between valproate metabolites and metabolites formed from the beta-oxidation of branched-chain amino acids (isoleucine, leucine, and valine) suggest that valproate may utilize key enzymes of branched-chain amino acid metabolism. Genetic deficiencies in these enzymes may decrease beta-oxidation of valproate and increase formation of valproate hepatotoxic metabolites. We attempted to determine if valproate interacts with branched-chain amino acid enzymes and also evaluated the effect of valproate on the urinary excretion of the straight-chain fatty acids butyrate (C4), valerate (C5), and hexanoate (C6). We collected dosage interval urine samples from three groups of 10 valproate patients: (1) valproate monotherapy, (2) valproate with carbamazepine, and (3) valproate with phenytoin. We also collected 12-hour urine samples from 10 normal volunteers who served as controls. Valproate caused a significant increase in the excretion of the deaminated acid metabolites of valine, isoleucine, and leucine. There were also significant increases in the excretion of the isoleucine metabolites 2-methylbutyrate and 2-methyl-3-OH-butyrate in the valproate patients. Valproate caused a significant increase in the excretion of all three of the straight-chain fatty acids evaluated, and valproate appears to inhibit the four types of acyl-CoA dehydrogenases involved in branched-chain amino acid and short- and medium-chain fatty acid metabolism.
Anderson
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GD
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Acheampong
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AA
Levy
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RH
D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000737:chemistry / Q000378:metabolism*; D002220:Carbamazepine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007532:Isoleucine / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D010672:Phenytoin / Q000627:therapeutic use; D014556:Urine / Q000737:chemistry; D014635:Valproic Acid / Q000627:therapeutic use*
D000597:Amino Acids, Branched-Chain; D007532:Isoleucine; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin