Metabolic conversion of 2-propylpentanal acetals to valproic acid in vitro. Model prodrugs of carboxylic acid agents.
As part of an investigation to test the feasibility of using acetals as precursors of acidic drugs, the dimethyl, diethyl, [2H10]diethyl, and diisopropyl acetals of 2-propylpentanal were synthesized and their metabolic conversion to the anticonvulsant, valproic acid (2-propylpentanoic acid), was investigated. The acetals were incubated with either 10,000g supernatant or microsomes isolated from rat liver. Data from the measurement of the metabolite, valproic acid, with selected ion monitoring gas chromatography/mass spectrometry indicated that the dimethyl, diethyl, [2H10]diethyl, and diisopropyl acetals were substrates. The amount of valproic acid produced from the incubation of 2-propylpentanal diethyl acetal with 10,000g supernatant was reduced by the cytochrome P-450 inhibitor, SKF-525A. The production of acid was also decreased by lack of NADPH or oxygen. These data are consistent with a cytochrome P-450 mediated reaction. 2-Propyl-1-pentanol was the major metabolite identified from microsomal preparations free of soluble fraction enzymes. A deuterium isotope effect calculated as the ratio of the amount of valproic acid produced from unlabeled and [2H5]ethyl-labeled substrate was 1.2. Failure to detect an ester as a metabolite of 3-phenylpropanal diethyl acetal along with the results of the isotope effect studies suggest that the mechanistic pathway of acyclic acetal metabolism involves oxidation of an ether methylene and not oxidation at the acetal carbon.
Vicchio
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Department of Medicinal Chemistry/Pharmacognosy, University of Maryland, Baltimore 21201.
Callery
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D000080:Acetals / Q000302:isolation & purification / Q000493:pharmacokinetics*; D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000493:pharmacokinetics*
D000080:Acetals; D002264:Carboxylic Acids; D011355:Prodrugs; C061821:2-propylpentanal dimethyl acetal; C061822:2-propylpentanal diethyl acetal; C061823:2-propylpentanal diisopropyl acetal; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System