Metabolic Changes of Drugs and Related Organic Compounds Oxidative Reactions 3 rd stage/ 1 st course Lecture 6 Shokhan J. Hamid
B. 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). 2
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. 3
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. N-acetyl 4
C. 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. 5
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. 6
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. 7
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. 8
8. 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. 9
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 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. 10
9. 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 ring (A) present in this steroid leads to the corresponding phenolic product 17-α ethinyl-18-homoestradiol as a minor metabolite in women. 11
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. 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. 12
B. REDUCTIVE REACTIONS
REDUCTIVE REACTIONS Reductive processes play an important role in the metabolism of many compounds containing carbonyl, nitro, and azo groups. Bioreduction of carbonyl compounds generates alcohol derivatives, whereas nitro and azo reductions lead to amino derivatives. The hydroxyl and amino moieties of the metabolites are much more susceptible to conjugation than the functional groups of the parent compounds. Hence, reductive processes, as such, facilitate drug elimination. 14
1. REDUCTION OF ALDEHYDE AND KETONE CARBONYLS The carbonyl moiety, particularly the ketone group, is encountered frequently in many drugs. In addition, metabolites containing ketone and aldehyde functionalities often arise from oxidative deamination of xenobiotics (e.g., propranolol, chlorpheniramine, amphetamine). Because of their ease of oxidation, aldehydes are metabolized mainly to carboxylic acids. Occasionally, aldehydes are reduced to primary alcohols. Ketones, however, are generally resistant to oxidation and are reduced mainly to secondary alcohols. Alcohol metabolites arising from reduction of carbonyl compounds generally undergo further conjugation (e.g., glucuronidation). 15
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Diverse enzymes, called aldo-keto reductases, carry out bioreduction of aldehydes and ketones. They are found in the liver and other tissues (e.g., kidney). Oxido-reductase enzymes that carry out both oxidation and reduction reactions also can reduce aldehydes and ketones. For example, the important liver alcohol dehydrogenase is an NAD+ dependent oxidoreductase that oxidizes ethanol and other aliphatic alcohols to aldehydes and ketones. In the presence of NADH or NADPH, however, the same enzyme system can reduce carbonyl derivatives to their corresponding alcohols. 17
Few aldehydes undergo bioreduction because of the relative ease of oxidation of aldehydes to carboxylic acids. However, one frequently cited example of a parent aldehyde drug undergoing extensive enzymatic reduction is the sedative hypnotic chloral hydrate. Bioreduction of this hydrated aldehyde yields trichloroethanol as the major metabolite in humans. Interestingly, this alcohol metabolite is pharmacologically active. Further glucuronidation of the alcohol leads to an inactive conjugated product that is readily excreted in the urine. 18
Aldehyde metabolites resulting from oxidative deamination of drugs also undergo reduction to a minor extent. For example, in humans the β-adrenergic blocker propranolol is converted to an intermediate aldehyde by N-dealkylation and oxidative deamination. Although the aldehyde is oxidized primarily to the corresponding carboxylic acid, a small fraction is also reduced to the alcohol derivative. 19
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2. REDUCTION OF NITRO AND AZO COMPOUNDS The reduction of aromatic nitro and azo xenobiotics leads to aromatic primary amine metabolites. Aromatic nitro compounds are reduced initially to the nitroso and hydroxylamine intermediates, as shown in the following metabolic sequence: 21
Azo reduction, however, is believed to proceed via a hydrazo intermediate (-NH-NH-) that subsequently is cleaved reductively to yield the corresponding aromatic amines: Bioreduction of nitro compounds is carried out by NADPHdependent microsomal nitro reductases present in the liver. A multicomponent hepatic microsomal reductase system requiring NADPH appears to be responsible for azo reduction. In addition, bacterial reductases present in the intestine can reduce nitro and azo compounds. 22
7-nitro benzodiazepine derivatives clonazepam and nitrazepam are metabolized extensively to their respective 7-amino metabolites in humans. 23
Bacterial reductases present in the intestine play a significant role in reducing azo xenobiotics, particularly those that are absorbed poorly. Accordingly, the two azo dyes tartrazine and amaranth have poor oral absorption because of the many polar and ionized sulfonic acid groups present in their structures. 24
3. MISCELLANEOUS REDUCTIONS Several minor reductive reactions also occur. Reduction of N-oxides to the corresponding tertiary amine occurs to some extent. For example, imipramine N-oxide undergoes reduction. 25
C. HYDROLYTIC REACTIONS Hydrolysis of Esters and Amides The metabolism of ester and amide linkages in many drugs is catalyzed by hydrolytic enzymes present in various tissues and in plasma. The enzymes carrying out ester hydrolysis include several non specific esterases found in the liver, kidney, and intestine as well as the pseudocholinesterases present in plasma. Amide hydrolysis appears to be mediated by liver microsomal amidase and esterases. 26
Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality, because of the relative ease of hydrolyzing the ester linkage. A classic example of ester hydrolysis is the metabolic conversion of aspirin (acetylsalicylic acid) to salicylic acid. 27
Of the two ester moieties present in cocaine, it appears that, the methyl group is hydrolyzed preferentially to yield benzoylecgonine as the major human urinary metabolite. Hydrolysis of cocaine to methylecgonine also occurs in plasma to a minor extent. 28
Amides are hydrolyzed slowly in comparison to esters. Hydrolysis of the amide bond of procainamide is relatively slow compared with hydrolysis of the ester linkage in procaine. 29
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