Yue - Drug metabolism

1st-pass effect = 1st-pass metabolism

phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.

Zone 1

• Periportal zone

• ⬆ High Oxygen

• ⬇ Low CYP450

• ⬆ High Glutathione

Zone 3

• Pericentral zone

• ⬇ Low Oxygen

• ⬆ High CYP450

• ⬇ Low Glutathione

Oxidations

Phase I

Reductions

Phase I

Hydrolysis

Phase I

Glucuronidation

Phase II

Sulfation

Phase II

Glutathione

Phase II

Amino Acid Conjugation

Phase II

Aceylation

Phase II

Methylation

Phase II

What metabolic reactions REDUCES water solubility?

1. Methylation

2. Acetylation

Phase I Metabolism

Functionalization → introduce/expose a functional group

• Think: “Modify” (make it ready)

Phase II metabolism

Conjugation → attach something/make it very polar

• Think: “Make it leave” (water soluble → excrete)

Which of the following statements about drug metabolism is NOT true?

A. Drug metabolism can affect drug activity.

B. Drug metabolism can affect drug toxicity.

C. Drug metabolism can affect drug excretion.

D. Drug metabolism always increase drug water solubility.

D. Drug metabolism always increase drug water solubility.

Glucuronidation

• Enzyme: UGT

• Co-factor: UDP

• Conjugating Agent: GA

Glucuronidation (purpose)

• Purpose: UGT adds a “tag” (glucuronide) to a drug so your body can get rid of it.

• Precursor: glucose

  • Glucose abundant in liver

Gray Baby Syndrome

Neonate does not have efficient UGTs → grow & stronger when they’re older

• Low UGT activity in babies → Chloramphenicol cannot be excreted efficiently → hypotension, blue/gray skin → “Gray Baby Syndrome”

Sulfation

• Enzyme: SULTs

• Co-factor: PAPS

• Conjugating agent: Sulfate group

Sulfation (purpose)

Glutathione

A DETOX “shield” in you body.

• Glutathione detoxifies harmful substances by binding them and making them easier to eliminate

Glutathione

A DETOX “shield” in you body.

• Glutathione detoxifies harmful substances by binding them and making them easier to eliminate

Acetylation

Acetylation an acetyl group to a drug to help process it

• Acetylation adds an acetyl group to help inactivate and process drugs

• REDUCE water solubility

  • Makes the drug less polar