Effect of Drug Pre-treatment on the Metabolism of Methyrapone.
Metyrapone (SU 488), an inhibitor of 11β - hydroxylase used an a diagnostic and therapeutic agent in the treatment of Cushing's disease, has been found to be metabolised in vivo in rats mainly to metyrapol via reductive mechanism and to the N.-oxides in oxidative mechanism. A significant sex difference as to the production of metyrapol was observed; being higher in the male rats (94 ± 1%) than in the female (64 ± 2%). The influence of drug pretreatment on the metabolism of metyrapone was investigated in the rats. It was observed that phenobarbital, ethanol and pregnenolone significantly (P< 0.05) caused an induction of the metyrapone N-oxide (B) in the male rats while anthracene did not cause any significant induction. Only ethanol significantly (P<0.05) induced the production of N-oxide A. On the other hand cimetidine a cytochrome P- 450 inhibitor and methimazole, an FAD (flavine Adenine dinucleotide) mediated inhibitor of cytochrome P-450, inhibited the formation of N-oxide (13) and slight increase in metyropol formation ccmpared to that produced in the inducers. In the female rats, only phenobarbital significantly (P < 0.05) induced the production of both N-oxides with a significant decrease in amount of metyrapol formed. While anthracene has no effect on the formation of both N-oxides of metyrapone, (though with increase in amount of metyrapol formed), ethanol, cimetidine and methimazole inhibited the production of metyrapone N-oxide (B) and (A) with a preferential increase in the amount of metyrapol formed. These then suggest a possibility of both FAD and cytochrome P-450 influence in the oxidative metabolism of metyrapone.