Oxidation Involving Carbonoxygen Systems

Oxidative O-dealkylation of carbon-oxygen systems (principally ethers) is catalyzed by microsomal mixed function oxidases.163 Mechanistically, the biotransformation involves an initial a-carbon hydroxylation to form either a hemiacetal or a hemiketal, which undergoes spontaneous carbon-oxygen

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bond cleavage to yield the dealkylated oxygen species (phenol or alcohol) and a carbon moiety (aldehyde or ketone). Small alkyl groups (e.g., methyl or ethyl) attached to oxygen are O-dealkylated rapidly. For example, morphine is the metabolic product of O-demethylation of codeine.249 The antipyretic and analgesic activities of phenacetin (see drawing of acetaminophen metabolism) in humans appear to be a consequence of O-deethylation to the active metabolite acetaminophen.250 Several other drugs containing ether groups, such as indomethacin (Indocin),251,252 prazosin (Minipress),253,254 and metoprolol (Lopressor),122,123 have reportedly undergone significant O-demethylation to their corresponding phenolic or alcoholic metabolites, which are further conjugated. In many drugs that have several nonequivalent methoxy groups, one particular methoxy group often appears to be O-demethy-lated selectively or preferentially. For example, the 3,4,5-trimethoxyphenyl moiety in both mescaline255 and trimetho-prim232 undergoes O-demethylation to yield predominantly the corresponding 3-O-demethylated metabolites. 4-O-demethylation also occurs to a minor extent for both drugs. The phenolic and alcoholic metabolites formed from oxida-tive O-demethylation are susceptible to conjugation, particularly glucuronidation.

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