Metabolism of mephentermine and its derivatives by the microsomal fraction from male Wistar rat livers.
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.
Mori
M A
MA
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
Kobayashi
M
M
Uemura
H
H
Mori
Y
Y
Miyahara
T
T
Kozuka
H
H
D000332:Aerobiosis; D000818:Animals; D002458:Cell Fractionation; D065607:Cytochrome P-450 Enzyme Inhibitors; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008616:Mephentermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors; D010645:Phentermine / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D009249:NADP; D010645:Phentermine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D008616:Mephentermine