Enzymes and phases of metabolism

Learning objective

Predict how enzyme induction or inhibition changes an active parent drug versus a prodrug, and explain the kidney-liver connection.

Transformation and exit are different

Metabolism changes chemical identity; excretion removes drug or metabolites from the body. Liver enzymes often make lipophilic molecules easier to eliminate, but metabolism does not always inactivate a drug. A metabolite may remain active, and a prodrug requires conversion to generate an active form. Some drugs are excreted substantially unchanged.

Phase I and phase II

Phase I reactions include oxidation, reduction and hydrolysis. Many, but not all, involve cytochrome P450 enzymes. Phase II reactions conjugate a molecule with another chemical group, often increasing water solubility. These labels classify reactions; they are not a compulsory two-step assembly line for every drug.

Induction and inhibition depend on what the enzyme does

Induction increases enzyme capacity over time. Inhibition reduces enzyme activity. For an active parent drug whose main clearance pathway is that enzyme, induction can lower exposure and inhibition can raise it. For a prodrug that needs that enzyme for activation, inhibition may instead reduce formation of the active product. Specify the substrate and pathway before predicting an effect.

Why the kidney matters

At the glomerulus, unbound small molecules can enter filtrate. As fluid travels through the nephron, some drug can return to blood through tubular reabsorption; secretion can also move drug into tubular fluid. More water-soluble metabolites are often less readily reabsorbed. Filtration is not the same as final urinary excretion. Renal and hepatic function can both change the time course.

Check your understanding

Explain it without notes

Describe the fate of a filtered molecule that is reabsorbed.

Explain why phase II need not follow phase I.

Revisit the connected course lessons and visuals

Enzyme induction, inhibition and variation

Prodrugs and first-pass metabolism

Excretion and the kidney-liver connection

Julien’s Primer of Drug Action, supplied consolidated PDF pages 10, 15, 16, 17 (Chapter 1). Locators refer to PDF captures, not printed pages. Original paraphrase and practice; source conformance reviewed, not independently clinically certified.