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PW-051 Xenobiotic & Drug Metabolism Biotransformation unreviewed

Phase I - Functionalization

Lipophilic xenobiotic/drug Oxidised, reduced or hydrolysed metabolite
Compartment
Smooth ER (microsomes), mitochondria
Main tissue
Liver mainly; intestine, lung, kidney
Rate-limiting
Cytochrome P450 monooxygenases (CYP)
Steps
3

Reaction steps

In source order, 3 total

showing 1–3
  1. 1

    Drug + O2 + NADPH -> hydroxylated/oxidized drug + H2O + NADP+

    Cytochrome P450 monooxygenases (CYP) 1.14.14.1 ST-0367 Irreversible/directional rate-limiting NADPH O2 heme CYP reductase
    In O2 NADPH
    Out Hydroxylated/oxidized drug H2O NADP+
    › Notes

    Smooth ER of hepatocytes. Introduces or exposes a polar group. CYP3A4 handles roughly half of all drugs.

  2. 2

    Ester or amide + H2O -> acid + alcohol/amine

    Esterases and amidases ST-0368 Irreversible/directional H2O
    In Ester or amide H2O
    Out Alcohol/amine
    › Notes

    Non-CYP hydrolysis, e.g. aspirin to salicylate.

  3. 3

    Amine + O2 + H2O -> aldehyde + NH3 + H2O2

    Monoamine oxidase (MAO-A/MAO-B) 1.4.3.4 ST-0369 Irreversible/directional FAD O2
    In Amine O2 H2O
    Out NH3 H2O2
    › Notes

    Outer mitochondrial membrane; MAO inhibition plus dietary tyramine causes hypertensive crisis.

Showing all 3 steps.

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