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Phase I reactions in Drug Metabolism

Phase I reactions in Drug Metabolism. Phases of metabolism. Phase 1 reactions. Oxidation Reduction Hydrolysis Substrate molecules changes, polarity increases and substrate gains a suitable structure for Phase 2 reactions. CARBON. Carbon oxidation. Aliphatic carbon

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Phase I reactions in Drug Metabolism

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  1. Phase I reactions in Drug Metabolism

  2. Phases of metabolism

  3. Phase 1 reactions • Oxidation • Reduction • Hydrolysis Substrate molecules changes, polarity increases and substrate gains a suitable structure for Phase 2 reactions.

  4. CARBON

  5. Carbon oxidation • Aliphatic carbon • Alicyclic carbon • Aromatic carbon • Alcohol • Aldehyde • Heterocyclic karbon • Oxidative O,S,N dealkylation

  6. Aliphatic carbon oxidation Alcohol Aldehyde Acid

  7. Ulgen, M. and J. W. Gorrod (1992). “Microsomal formation of N-benzyl-4-hydroxymethylaniline from N-benzyl-4- methylaniline.” J Pharm Pharmacol44(10): 865-6.

  8. Alicyclic carbon oxidation

  9. Aromatic carbon oxsidation

  10. Ulgen, M., J. W. Gorrod, et al. (1994). “Structure-activity relationships in the formation of amides from substituted N-benzylanilines.” Xenobiotica24(8): 735-48.

  11. Alcohol and aldehyde oxidation Alcohol Aldehyd Carboxylic acid

  12. Heterocyclic carbon oxidation

  13. Oxidative O,S and N-dealkylation Aldehid X = O Ether X = S Thioether X = NH Sec. amine X = O Alcohol X = S Thioalcohol X = NH Pr. amine

  14. Low, C. M., M. Ulgen, et al. (1994). “The recognition of a diarylimine as a metabonate produced during incubation of N-benzyl-4-chloroaniline with hepatic microsomal preparations.” J Pharm Pharmacol46(7): 585-90.

  15. Kucukguzel, I., M. Ulgen, et al. (1999). “In vitro hepatic microsomal metabolism of N-benzyl-N-methylaniline.” Farmaco54(5): 331-7.

  16. NITROGENE

  17. Nitrogene oxidation • Amine • Azo • Imine • Amide

  18. Amine oxidation

  19. Tunc, N., F. Yilmaz, et al. (1997). “In vitro metabolic N- and C-oxidation of phenanthridine.” Eur J Drug Metab Pharmacokinet22(4): 345-9.

  20. Yilmaz, F., M. Ulgen, et al. (1999). “The in vitro hepatic microsomal metabolism of N-benzyladamantanamine in rats.” Drug Metabol Drug Interact15(2-3): 115-25.

  21. Kucukguzel, I., Ulgen, M. (1998). “In vitro metabolic fate of N-substituted Dibenzylamines : Investigation of Biological Oxidation Site on Nitrogen Compounds with Different pKa.” J. Fac. Pharm. Ist32: 69-86.

  22. Azo group oxidation

  23. Kaymakcioglu, B., E. Oruc, et al. (1999). “The in vitro hepatic microsomal metabolism of 3,5-dimethyl-4- (phenylazo)-(1H)-pyrazole in rats.” Drug Metabol Drug Interact15(2-3): 107-14.

  24. Imine oxidation

  25. Gorrod, J. W. and M. Ulgen (1994). “Metabolic N-oxidation of diarylimines: a new metabolic reaction of potential toxicological significance.” Drug Metab Rev26(1-2): 241-52.

  26. Amide oxidation

  27. SULPHUR

  28. Sulphur oxidation • Thioalcohols (thioles) • Thioethers (sulphides) • Thioamides

  29. Thioalcohol (thiol) oxidation

  30. Tthioether (sulphide) oxidation

  31. Thioamide oxidation

  32. Groups undergoingreduction • Nitro • Azo • Carbonyl • N-oxide • Carbon linked with nitrogen • Disulphur

  33. Nitro reduction

  34. Azo reduction

  35. Carbonyl reduction

  36. Yilmaz, F., Ulgen, M., Dogruer, D,S., Çakir, B., Şahin, M.F. (1999). “The in vitro hepatic metabolism of 1-phenyl-2-(2-benzothiazolinone-3-yl)ethanone and their reduced derivatives.” Experimental and Toxicological Pathology51: 178-181.

  37. N-oxide reduction

  38. Reductive dehalogenization

  39. Cleavage of S-S bond

  40. Groups undergoing hydrolysis • Amide • Ester • Epoxide • Sulfonamide • Imine • Hydrazone • Hydrazide

  41. Ester hydrolysis R-COOR1 + H2O  R-COOH + R1-OH asit alkol

  42. Ulgen, M., Yilmaz, F., Dogruer, D.S., Şahin, M.F. (1999). “The in vitro hepatic microsomal metabolism of methyl 2-(2(3H)- benzoxazolone-3-yl)acetate in rats.” Drug Metab. Drug Interact.15: 173-179.

  43. Amide hydrolysis R-CONH2 + H2O  R-COOH + NH3 asit amonyak

  44. Ulgen, M., Erçak, K., Küçükgüzel, I., Gorrod, J.W. "In vitro microsomal metabolic studies on secondary aromatic amides" Boll.Chim.Farm., 136, 239-243 (1997).

  45. Epoxide hydrolysis Diol

  46. Sulfonamide hydrolysis

  47. Imine hydrolysis

  48. Gorrod, J. W. and M. Ulgen (1994). “Metabolic N-oxidation of diarylimines: a new metabolic reaction of potential toxicological significance.” Drug Metab Rev26(1-2): 241-52.

  49. Hydrazone hydrolysis

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