1. Metabolic Changes of Drugs and Related Organic Compounds
Lecture /5

2. 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.

3. 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).

5. 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).
these soluble enzymes have similar physiochemical properties and broad substrate specificities and require NADPH as a cofactor.
Oxidoreductase 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.

6. 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.

7. 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

9. 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:

10. 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 NADPH-dependent microsomal and soluble 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.

11. 7-nitro benzodiazepine derivatives clonazepam and nitrazepam are metabolized extensively to their respective 7-amino metabolites in humans.

12. 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.

13. 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 in rat liver.

14. The anti-inflammatory agent sulindac undergoes reduction to an active sulfide that is responsible for the overall anti inflammatory effect of the parent drug.
Sulindac exhibits little anti-inflammatory activity.

15. Hydrolysis of Esters and Amides
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 amidases, esterases, and deacylases.

16. Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality.
This is 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.

17. Of the two ester moieties present in cocaine, it appears that, in general, the methyl group is hydrolyzed preferentially to yield benzoylecgonine as the major human urinary metabolite.
The hydrolysis of cocaine to methylecgonine, however, also occurs in plasma and, to a minor extent, blood.

18. 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.

19. Miscellaneous Hydrolytic Reactions
Hydrolysis of recombinant human peptide drugs and hormones at the N- or C- terminal amino acids by carboxypeptidase and aminopeptidase and proteases in blood and other tissues is a well-recognized hydrolytic reaction.
Examples of peptides or protein hormones undergoing hydrolysis include human insulin, growth hormone (GH), prolactin, parathyroid hormone (PTH), and atrial natriuretic factor (ANF).

20. Miscellaneous Bioactivation of Prodrugs
Chemical activation of Proton pump inhibitors.
The highly acidic environment in and around the parietal cell allows for protonation of nitrogen on the benzimidazole ring, followed by attachment of the pyridine nitrogen.
Ring opening of the intermediate then yields the sulfenic acid that subsequently cyclizes with the loss of water.
This intermediate is highly susceptible to nucleophilic attack by the SH moieties of the cysteine residues associated with proteins, including the proton pump of the parietal cells.

23. END