Abstract
Complexation of ferrous cytochrome P450 by metabolic intermediates formed during NADPH−catalyzed metabolism of compounds structurally related to orphenadrine was studied. This so−called metabolic intermediate complexation was determined in rat liver microsomes, obtained from phenobarbital−pretreated rats, at 455nm using 33 μM of the orphenadrine derivatives. Using secondary amine derivatives with various N−alkyl substituents, a parabolic relationship between the logarithm of percentage of cytochrome P450 complexation and hydrophobic fragmental constant was observed. The derivative with a bulky tertiary butyl group, however, was devoid of metabolic intermediate−complexing activity. This indicates that steric factors besides lipid solubility may govern the complexing activity; also substitution at the phenyl group affects metabolic intermediate complex formation.
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