Wirkungen von Metyrapon auf den Arzneimittelstoffwechsel und einige andere Funktionen der Leberzelle

Kinetic experiments on the binding of metyrapone to liver microsomes

Kinetic experiments on the inhibition of oxidative microsomal O- and N-demethylations by metyrapone (2-methyl-1, 2-bis(3-pyridyl)-l-propanone, Su 4885) were carried out using mouse liver microsomes as the enzyme source. The model substrates were p-nitroanisole and N-monomethyl-p-nitroaniline. It was shown that the inhibition is competitive. The K i for metyrapone is 0.42 × 10−4 M and for the reduced metabolite of metyrapone 1.15×10−4 M. Their spectral dissooiation constants as determined from difference spectra have almost the same values. From this it is concluded that the degree of inhibition is correlated to the amount of metyrapone bound to cytochrome P-450. Metyrapone does not seem to …

Influence of disulfiram on oxidative drug demethylation.

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, 19…