6533b85efe1ef96bd12bfc67

RESEARCH PRODUCT

Influence of disulfiram on oxidative drug demethylation.

subject

description

In clinical antiepileptie therapy it has been observed that the simultaneous administration of diphenylhydantoin and various other drugs causes toxic reactions to diphenylhydantoin. I t was found that disulfiram (Olesen, 1966) as well as ehloramphenieol (Christensen and Skovsted, 1969) cause toxic effects in patients treated with diphenylhydantoin. They are attributed to an increased concentration of diphenylhydantoin in the plasma. Analogous observations show that chloramphenieol enhances the clinical effects of tolbutamide and dicoumarol (Christensen and Skovsted, 1969). Since diphenylhydantoin is metabolized chiefly by p-hydroxylation to 5-(p-hydroxyphenyl)-5-phenyl-hydantoin (Butler, 1957) and also to a dihydro-diol compound (Chang et al., 1970), it is to be expected that disulfiram increases the serum levels of diphenylhydantoin by interfering with its hepatic hydroxylation. In our respective experiments, however, disulfiram and its metabolite diethyldithioearbamate interfered with the chemical determination of the diphenylhydantoin hydroxylation with the aid of Folin-Ciocalteu's reagent (Folin and Ciocalteu, 1927) by simulating the presence of phenolic hydroxyl groups. Since it can be assumed that the apparent inhibition of hepatic drug hydroxylation in vivo by disulfiram and ehloramphenieol is a more general phenomenon, we tried to detect this inhibition also in other hydroxylation reactions. The substrates chosen for these studies were aminopyrine for in vivo experiments and p-nitroanisole for in vitro tests (Honjo and Netter, 1969). The former serves as a model drug for oxidative N-demethylation and the latter for O-demethylation. In order to determine the plasma levels of the aminopyrine metabolite 4aminoantipyrine the carotid artery of male Sprague-Dawley rats was eannulated with fine polyethylene tubing for repeated blood drawing from the heparinized non-anesthetized animal. After each sampling of about 1.5 ml of blood the erythrocytes were resuspended in saline and reinjeeted, while the plasma was used for the determination of the 4-aminoantipyrine concentration according to (Brodie and Axelrod, 1950) after acid hydrolysis of the aeetylated portion of the total 4-aminoantipyrine. Disulfiram was applied orally by feeding a 1 ~/o tragaeanth suspension of the poorly water soluble substance. I t was given 15 hrs prior to the administration of aminopyrine.