Reaction Mechanisms Drug Metabolism biochemical modification of drugs
Reaction Mechanisms Drug Metabolism • biochemical modification of drugs through enzymatic systems to convert lipophilic molecules into more polar structures • Phase I …… biotransformations …… introduce polarity in drug molecules …… oxidations, reduction, hydrolysis, etc. • Phase II …… conjugations …… interaction with polar groups (phase I) …. . glucuronidation, sulfonation, etc. MEDC 527 Fall 2008 1
Reaction Mechanisms Drug Metabolism … Phase II Conjugations • Glucuronidation …… UDP-glucuronosyltransferase • Sulfonation (Sulfation) …… sulfotransferases • Glutathionylation …… glutathione S-transferase MEDC 527 Fall 2008 2
Reaction Mechanisms Drug Metabolism … Phase I • Hydrolysis …… carboxyesterases …… amidases …… epoxide hydrolyases • Oxidations …… cytochrome P 450 monooxygenase (CYP 450) …… flavin-containing monooxygenase (FMO) …… alcohol & aldehyde dehydrogenase …… monoamine oxidase …… peroxidase • Reductions …… NADPH-cytochrome P 450 reductase …… Reduced (ferrous) cytochrome P 450 MEDC 527 Fall 2008 3
Phase I Metabolism Reactions Hydrolysis by Carboxyesterases, peptidases, etc. • Hydrolysis of amide and its derivatives ‘p. H conditions will define the charge on group(s)’ • Ester Hydrolysis ‘p. H conditions will define the charge on group(s)’ MEDC 527 Fall 2008 4
Phase I Metabolism Reactions Hydroxylations Catalyzed by CYP 450 • Generalized Reaction for Mono-oxygenases R-H + O 2 + NADPH + H+ R-OH + NADP+ + H 2 O • Aromatic Hydroxylations • Aliphatic Hydroxylations MEDC 527 Fall 2008 5
![Reaction Mechanisms Hydroxylations Catalyzed by CYP 450 • Deamination [OH] • O-Dealkylation [OH] •](http://slidetodoc.com/presentation_image/40eca9bceadf85f5f8d089e61b8d7686/image-6.jpg "Reaction Mechanisms Hydroxylations Catalyzed by CYP 450 • Deamination [OH] • O-Dealkylation [OH] •")
Reaction Mechanisms Hydroxylations Catalyzed by CYP 450 • Deamination [OH] • O-Dealkylation [OH] • N-Dealkylation [OH] MEDC 527 Fall 2008 6
![Reaction Mechanisms Hydroxylations Catalyzed by CYP 450 • N-Oxidation [OH] • Sulfoxidation [OH] •](http://slidetodoc.com/presentation_image/40eca9bceadf85f5f8d089e61b8d7686/image-7.jpg "Reaction Mechanisms Hydroxylations Catalyzed by CYP 450 • N-Oxidation [OH] • Sulfoxidation [OH] •")
Reaction Mechanisms Hydroxylations Catalyzed by CYP 450 • N-Oxidation [OH] • Sulfoxidation [OH] • Epoxidation [OH] MEDC 527 Fall 2008 7
Reaction Mechanisms Prosthetic Group of CYP 450 … Heme MEDC 527 Fall 2008 8
Reaction Mechanisms Hydroxylation of RH by CYP 450 R-H R-OH Fe+3 Fe+4 -OH CYP 450 R Fe+3 CYP 450 H-R CYP 450 e- Fe+5=O Fe+2 H-R CYP 450 O 2 H 2 O H+ Fe+3. . . OOH H-R Fe+2…O 2 CYP 450 Fe+3…O 2 H-R CYP 450 e. MEDC 527 Fall 2008 9
- Slides: 9