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Reaction Mechanisms

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

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Reaction Mechanisms

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  1. 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

  2. Reaction Mechanisms Drug Metabolism … Phase II Conjugations • Glucuronidation • …… UDP-glucuronosyltransferase • Sulfonation (Sulfation) • …… sulfotransferases • Glutathionylation • …… glutathione S-transferase MEDC 527 Fall 2008

  3. Reaction Mechanisms Drug Metabolism … Phase I • Hydrolysis • …… carboxyesterases • …… amidases • …… epoxide hydrolyases • Oxidations • …… cytochrome P450 monooxygenase (CYP450) • …… flavin-containing monooxygenase (FMO) • …… alcohol & aldehyde dehydrogenase • …… monoamine oxidase • …… peroxidase • Reductions • …… NADPH-cytochrome P450 reductase • …… Reduced (ferrous) cytochrome P450 MEDC 527 Fall 2008

  4. Phase I Metabolism Reactions Hydrolysis by Carboxyesterases, peptidases, etc. • Hydrolysis of amide and its derivatives • Ester Hydrolysis ‘pH conditions will define the charge on group(s)’ ‘pH conditions will define the charge on group(s)’ MEDC 527 Fall 2008

  5. Phase I Metabolism Reactions Hydroxylations Catalyzed by CYP450 • Generalized Reaction for Mono-oxygenases • R-H + O2+ NADPH + H+R-OH + NADP++ H2O • Aromatic Hydroxylations • Aliphatic Hydroxylations MEDC 527 Fall 2008

  6. [OH] [OH] [OH] [OH] Reaction Mechanisms Hydroxylations Catalyzed by CYP450 • Deamination • O-Dealkylation • N-Dealkylation MEDC 527 Fall 2008

  7. [OH] [OH] Reaction Mechanisms Hydroxylations Catalyzed by CYP450 • N-Oxidation • Sulfoxidation • Epoxidation [OH] MEDC 527 Fall 2008

  8. Reaction Mechanisms Prosthetic Group of CYP450 … Heme MEDC 527 Fall 2008

  9. Reaction Mechanisms Hydroxylation of RH by CYP450 R-H R-OH Fe+3 CYP450 Fe+4-OH Fe+3 R H-R CYP450 CYP450 e- Fe+2 H-R Fe+5=O H-R CYP450 CYP450 O2 H2O H+ Fe+3...OOH H-R Fe+2…O2 H-R CYP450 CYP450 Fe+3…O2 H-R CYP450 e- MEDC 527 Fall 2008

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