Modification of the acute effects of ethanol or acetaldehyde on drug metabolism by ascorbic acid, thiamine, or cysteine in vivo Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/4q77fv34h

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  • The inhibition of mixed-function oxidase (MFO) activity by ethanol or acetaldehyde was examined in vivo by monitoring changes in salivary half-life of antipyrine or aminopyrine in adult male Sprague-Dawley rats. Ethanol (1-6 g/kg, po) or acetaldehyde (4-8 mmol/kg, ip) was administered 20 minutes prior to antipyrine (100 mg/kg, ip) or aminopyrine (80 mg/kg, ip). Ethanol increased the half-life of antipyrine in a dose-dependent (0-96%) manner. The effect of acetaldehyde was minimal (23%) and not dose-dependent. Neither compound affected the half-life of aminopyrine. L-ascorbic acid (2 mmol/kg), thiamine-HC1 (0.24 mmol/kg), or L-cysteine (2 mmol/kg) was given ip 90 minutes prior to ethanol (2 g/kg, po) or acetaldehyde (6 mmol/kg, ip) which was followed in 20 minutes by antipyrine. Ascorbic acid or cysteine pretreatments effectively prevented the ethanol-increased antipyrine half-life. Other pretreatments had only a weak affect on ethanol- or acetaldehyde- increased antipyrine half-life. Cysteine did not affect acetaldehyde-increased antipyrine half-life. The data suggested a possible direct effect of ethanol on the WO metabolism of antipyrine. Low concentrations of either ethanol (10 mM) or acetaldehyde (1.4 mM) did not inhibit the N-demethylation of either aminopyrine to monomethy1-4-aminoantipyrine or antipyrine to norantipyrine (NOR) in isolated rat liver microsomes. The hydroxylation of antipyrine to 3-hydroxymethylantipyrine (3 AMA) was increased by 57% and 19% respectively. Ethanol (50 mM) did not inhibit the metabolism of antipyrine as measured by the oxidation of NADPH to NADP⁺, but did result in a 20% decrease in the formation of NOR and a 24% decrease in the formation of 3 AMA. The inability of in vitro assays to quantify the 4-hydroxyantipyrine metabolite of antipyrine may explain the lack of effect by low concentrations of ethanol or acetaldehyde on in vitro antipyrine metabolism.
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