Abstract
1. The N-demethylation of mephentermine (MP), p-hydroxymephentermine (p-hydroxy-MP) and N-hydroxymephentermine (N-hydroxy-MP), to produce phentermine (Ph), p-hydroxyphentermine (p-hydroxy-Ph) and N-hydroxyphentermine (N-hydroxy-Ph), and the p-hydroxylation of MP and Ph, to produce p-hydroxy-MP and p-hydroxy-Ph, were examined using rat liver microsomal preparations containing NADPH. Microsomal reduction of N-hydroxy-Ph to Ph was also examined using various cofactors. In addition, enzymic system for the N-demethylation and p-hydroxylation were examined using various inhibitors. 2. N-Hydroxy-MP demethylation to N-hydroxy-Ph proceeded at a rate almost 10-fold faster than other reactions. MP demethylation to Ph, MP oxidation to P-hydroxy-MP, Ph oxidation to p-hydroxy-Ph proceeded at similar rates, whilst p-hydroxy-MP demethylation to p-hydroxy-Ph was catalysed at the slowest rate. Microsomal reduction of N-hydroxy-Ph to Ph required NADH, and the activity was similar to that of MP oxidation to p-hydroxy-MP. 3. N-Demethylation of MP, p-hydroxy-MP and N-hydroxy-MP were inhibited not only by inhibitors of cytochrome P450, but also by methimazole, an inhibitor of the FAD-monooxygenase system. p-Hydroxylations of MP and Ph were inhibited only by inhibitors of cytochrome P450.
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