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 Pharmacol 44(10):

8. Alicyclic carbon oxidation

9. Aromatic carbon oxsidation

10. Ulgen, M. , J. W. Gorrod, et al. (1994)
Ulgen, M., J. W. Gorrod, et al. (1994). “Structure-activity relationships in the formation of amides from substituted N-benzylanilines.” Xenobiotica 24(8):

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 Pharmacol 46(7):

15. Kucukguzel, I. , M. Ulgen, et al. (1999)
Kucukguzel, I., M. Ulgen, et al. (1999). “In vitro hepatic microsomal metabolism of N-benzyl-N-methylaniline.” Farmaco 54(5):

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 Pharmacokinet 22(4):

20. Yilmaz, F., M. Ulgen, et al. (1999). “The in vitro hepatic microsomal metabolism of N-benzyladamantanamine in rats.” Drug Metabol Drug Interact 15(2-3):

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. Ist 32:

22. Azo group oxidation

23. Kaymakcioglu, B. , E. Oruc, et al. (1999)
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 Interact 15(2-3):

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 Rev 26(1-2):

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 undergoing reduction
Nitro
Azo
Carbonyl
N-oxide
Carbon linked with nitrogen
Disulphur

33. Nitro reduction

34. Azo reduction

36. Carbonyl reduction

37. Yilmaz, F. , Ulgen, M. , Dogruer, D,S. , Çakir, B. , Şahin, M. F
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 Pathology 51:

38. N-oxide reduction

39. Reductive dehalogenization

40. Cleavage of S-S bond

41. Groups undergoing hydrolysis
Amide
Ester
Epoxide
Sulfonamide
Imine
Hydrazone
Hydrazide

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

43. Ulgen, M. , Yilmaz, F. , Dogruer, D. S. , Şahin, M. F. (1999)
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:

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

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

46. Epoxide hydrolysis
Diol

47. Sulfonamide hydrolysis

48. Imine hydrolysis

49. Gorrod, J. W. and M. Ulgen (1994). “Metabolic N-oxidation of diarylimines: a new metabolic reaction of potential toxicological significance.” Drug Metab Rev 26(1-2):

50. Hydrazone hydrolysis

51. Ulgen, M., Durgun, B.B., Rollas, S., Gorrod, J.W.
"The in vitro hepatic microsomal metabolism of benzoic acid benzylidene
hydrazide"
Drug Metab. Drug Interact., 13, (1997).

52. Hydrazide hydrolysis

53. Küçükgüzel, G., Küçükgüzel, İ., Ülgen, M.
“Metabolic and chemical studies on N-(4-chlorobenzyl)-N’-benzoylhydrzine”
Farmaco, 55, (2000).