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Drug Metabolism

Drug Metabolism. Where? First-Pass Effect More than 1 metabolite! Varies depending on species, age, gender, genetic variation, disease. Phase I Oxidations Reductions Hydrolysis. Phase II Synthetic/Conjugation. Phases of Drug Metabolism. Phase I Oxidations.

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Drug Metabolism

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  1. Drug Metabolism • Where? • First-Pass Effect • More than 1 metabolite! • Varies depending on species, age, gender, genetic variation, disease

  2. Phase I Oxidations Reductions Hydrolysis Phase II Synthetic/Conjugation Phases of Drug Metabolism

  3. Phase I Oxidations • Hydroxylations of N, C, S atoms • N-, O-, and S- dealkylations • Oxidative Deaminations • ROH RCHO RCOOH

  4. Phase I Oxidations: The Enzymes • Mixed Function Oxygenases found in smooth ER, e.g. Cytochrome P-450 • Microsomal Flavin Monoxygenase (FMO) • Alcohol Dehydrogenase • Xanthine Oxidase • Monoamine Oxidase (mitochondria)

  5. Oxidative Deamination/Dealkylations • Can occur on N-, O-, S-, or X- systems • Begins with hydroxylation, followed by elimination • Cytochrome P450 & MAO

  6. Other types of oxidative Reactions • ROH  RCHORCOOH • RSHRSSR • Desulfuration (C=S C=O)

  7. Hydrolysis • Nonspecific esterases, amidases • Amides hydrolyze more slowly than esters • May be stereospecific • Occurs in cytosol of cells (liver, kidney, intestine) and in plasma

  8. Hydrolysis

  9. Reductions • Less common than oxidations • Usually specific enzymes, e.g. aldo-keto reductases, nitro reductases • C=O  alcohols • NO2  NH2 • N=N  2 NH2

  10. Reductions

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