Metabolic Changes of Drugs and Related Organic Compounds Lecture / 4

OXIDATION INVOLVING CARBON–OXYGEN SYSTEMS Oxidative O-dealkylation of carbon–oxygen systems is catalyzed by microsomal mixed function oxidases. The biotransformation involves an initial α-carbon hydroxylation to form either a hemiacetal or a hemiketal, which undergoes spontaneous carbon–oxygen bond cleavage to yield the dealkylated oxygen species (phenol or alcohol) and a carbonyl moiety (aldehyde or ketone).

Small alkyl groups (e.g., methyl or ethyl) attached to oxygen are O- dealkylated rapidly. Morphine is the metabolic product of O-demethylation of codeine. The antipyretic and analgesic activities of phenacetin in humans appear to be a consequence of O-deethylation to the active metabolite acetaminophen.

In many drugs that have several nonequivalent methoxy groups, one particular methoxy group often appears to be O-demethylated selectively. For example, the 3,4,5-trimethoxyphenyl moiety in both mescaline and trimethoprim undergoes O-demethylation to yield predominantly the corresponding 3-O-demethylated metabolites. 4-Odemethylation also occurs to a minor extent for both drugs. The phenolic and alcoholic metabolites formed from oxidative O- demethylation are susceptible to conjugation, particularly glucuronidation.

OXIDATION INVOLVING CARBON–SULFUR SYSTEMS Carbon–sulfur functional groups are susceptible to metabolic S- dealkylation, desulfuration, and S-oxidation reactions. The first two processes involve oxidative carbon–sulfur bond cleavage. S-dealkylation is analogous to O- and N-dealkylation mechanistically (i.e., it involves α-carbon hydroxylation). For example, 6-(methylthio)purine is demethylated oxidatively in rats to 6-mercaptopurine.

Oxidative conversion of carbon–sulfur double bonds (C=S) (thiono) to the corresponding carbon–oxygen double bond (C=O) is called desulfuration. A well-known drug example of this metabolic process is the biotransformation of thiopental to its corresponding oxygen analog pentobarbital.

An analogous desulfuration reaction also occurs with the P=S moiety present in several organophosphate insecticides, such as parathion. Desulfuration of parathion leads to the formation of paraoxon, which is the active metabolite responsible for the anticholinesterase activity of the parent drug. The mechanistic details of desulfuration are poorly understood, but it appears to involve microsomal oxidation of the C=S or P=S double bond.

S-oxidation constitutes an important pathway in the metabolism of the H2-histamine antagonists cimetidine and metiamide. The corresponding sulfoxide derivatives are the major human urinary metabolites.

Oxidation of Alcohols and Aldehydes Many oxidative processes (e.g., benzylic, allylic, alicyclic, or aliphatic hydroxylation) generate alcohol or carbinol metabolites as intermediate products. If not conjugated, these alcohol products are further oxidized to aldehydes (if primary alcohols) or to ketones (if secondary alcohols). Aldehyde metabolites undergo oxidation to generate carboxylic acid derivatives.

Although secondary alcohols are susceptible to oxidation, this reaction is not often important because the reverse reaction, namely, reduction of the ketone back to the secondary alcohol, occurs quite readily. In addition, the secondary alcohol group, being polar and functionalized, is more likely to be conjugated than the ketone moiety. The bioconversion of alcohols to aldehydes and ketones is catalyzed by alcohol dehydrogenases present in the liver and other tissues.

Other Oxidative Biotransformation Pathways In addition to the many oxidative biotransformations discussed previously oxidative aromatization or dehydrogenation and oxidative dehalogenation reactions also occur. Metabolic aromatization has been reported for norgestrel. Aromatization or dehydrogenation of the A ring present in this steroid leads to the corresponding phenolic product 17-α ethinyl-18-homoestradiol as a minor metabolite in women.

In mice, the terpene ring of Δ1-THC undergoes aromatization to give cannabinol.

Many halogen-containing drugs and xenobiotics are metabolized by oxidative dehalogenation. For example, the volatile anesthetic agent halothane is metabolized principally to trifluoroacetic acid in humans. It has been postulated that this metabolite arises from CYP mediated hydroxylation of halothane to form an initial carbinol intermediate that spontaneously eliminates hydrogen bromide (dehalogenation) to yield trifluoroacetyl chloride.

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