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Metabolism

Metabolism. Terodiline. Aromatic p-hydroxylation predominate with R but benzylic hydroxylation is preferred with S (homework). Reduction. Play an important role in the metabolism of compounds containing azo , nitro, and carbonyl Reduction A- Reduction of aldehyde and ketones

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Metabolism

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  1. Metabolism

  2. Terodiline • Aromatic p-hydroxylation predominate with R but benzylic hydroxylation is preferred with S (homework)

  3. Reduction • Play an important role in the metabolism of compounds containing azo, nitro, and carbonyl • Reduction A- Reduction of aldehyde and ketones B- Reduction of nitro and azo compounds C- Reduction of sulfones

  4. Azo reduction

  5. Nitro reduction

  6. Aldehyde and ketones (CO)

  7. Reduction of sulfone

  8. N.B sometimes Sulphur metabolized to O

  9. Hydrolytic reactions A-Esters hydrolysis B- Amide hydrolysis • One of the major biotransformation reactions • Carried out by non specific esterases found in kidney, liver and intestine (and pseudo choline esterase in plasma) • Amides undergo hydrolysis by liver microsomal amidases, and esterases. • Amides hydrolyzed more slowly than esters.

  10. I-Ester hydrolysis

  11. 2-Amide hydrolysis

  12. Effect of metabolism on therapeutic activity • Imipramine----desipramine (more antidepressant) • Iproniazid (antidepressant)--------- INH (anti T.B)

  13. Phase II reactions • Glucuronide conjugation • Sulphate conjugation • Acetylation and acylation • Glycine conjugation • Glutathion • ( not all in the liver)

  14. Glucuronide conjugation • Liver enzyme catalyze synthesis of uridenediphosphateglucoronic acid (UDPGA) • It affect OH,SH,COOH,CONH • Xenobiotic reacts with the activated form of glucuronic acid (UDPGA) to form highly water soluble conjugate. This reaction is catalysed by microsomal uridinediphosphateglucuranyltransferase(UDPG-transferase).

  15. Sulphate conjugation • For phenols, alcohols and amines. • It originates from the body sulfate pole. Activated by conjugation with ATP to form 3-phosphoadenosine-5-phosphosulfate(PAPS) • Then the sulfate moiety of PAPS bind to OH----------under the effect of sulphotransferase

  16. Acylation reactions • Occur with NH2,OH and SH

  17. Although water solubility is not increased ,it helps in terminating the pharmacological activity of the drug or its amino metabolite. • Acetyl transferase is found in many tissues e.g liver

  18. Amino acid conjugation • Amino acid glycine and glutamine are most common. • For COOH and aromatic acids • Amino acids are not converted to activated enzymes but COOH is activated with ATP and CoAto form acylCoA which acylate A.A

  19. Glutathione and mercaptouric acid conjugation • GSH is a thiol containing tripeptide • It plays an important role in detoxification(for electrophilic compounds).(caused by the presence of electron with drowing groups as X,NO2,NO3,epoxide) • It protect vital constituents by its nucleophilic SH gp. • Conjugation is catalyzed by glutathione S-transferase. • Degradation of GSH conjugates ----to mercaptouric acid by microsomal enzymes

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