(4) Drug Metabolism

Drug Metabolism

Purpose

• Drug metabolism chemically changes a drug and usually prepares it for excretion.

• Most commonly, metabolism decreases or eliminates drug activity.

• Other possible results:

  • drug activity is maintained → may contribute to a longer duration

  • drug activity increases → less common

  • an inactive prodrug becomes active

Drug Metabolism

Overall goal:

Drug → add/expose a polar functional group → increase water solubility → eliminate the drug

• The body commonly tries to create or expose an oxygen-containing group:

  • alcohol

  • phenol

  • carboxylic acid

Drug Metabolism

Where occurs?

• Liver = main metabolic powerhouse.

• Gut = another major site, especially for orally administered drugs.

  • Gut metabolism can prevent some drugs from surviving oral administration.

• The professor said metabolism can occur in the CNS and essentially any organ, but emphasized the liver and gut.

Drug Metabolism

Phase I vs Phase II

Phase I	Phase II
Many different reactions are possible	Conjugation reaction joins two molecules
Multiple Phase I reactions may occur on one drug	Usually one Phase II reaction occurs before excretion
Adds or exposes a polar functional group	Adds a polar conjugate
Can activate, maintain, increase, decrease, or eliminate drug activity	Usually completes the metabolic pathway discussed

What enzyme perform many Phase I oxidation reactions?

• CYP = cytochrome P450.

• For this lecture, think of CYP as an enzyme that commonly:

  • adds OH, or

  • removes a small group to expose OH or NH

Factors that can change metabolism

• Age

• Gender

• Diet/nutritional status

• Disease states

• Environmental chemicals

• Two factors emphasized most

  • Co-administered drugs

  • Pharmacogenomics

Factors that can change metabolism

Co-administered drugs

• Two drugs may compete for the same metabolic enzyme.

• One drug may not be metabolized normally → its concentration stays higher for longer.

• With repeated doses, the concentration may continue rising → possible toxicity.

Factors that can change metabolism

Pharmacogenomics

• Patients can have different amounts or activity of metabolic enzymes.

• If a prodrug requires an enzyme that the patient has low activity of:

  • poor activation → reduced drug effect

Oxidation =
Reduction =

Oxidation = add oxygen, remove H
Reduction = remove oxygen, add H

Major Phase I reactions and enzymes

Reaction type	Main enzymes emphasized	What happens
Oxidation	CYP; alcohol dehydrogenase; aldehyde dehydrogenase; MAO	Adds/exposes oxygen or removes an amine
Reduction	Aldo-keto reductase	Common example: ketone → alcohol
Hydrolysis	Mainly esterases in this discussion	esterases commonly hydrolyze esters the professor emphasized that amides are much more stable

What’s body’s main metabolic approach?

• Oxidation

What are all are the Phase 1 Oxidation called?

1. Aromatic hydroxylation

2. Benzylic hydroxylation

3. Aliphatic/alicyclic hydroxylation

4. O-dealkylation

5. N-dealkylation

6. Deamination

• Alcohol/aldehyde oxidation

What are all are the Phase 1 Reduction called?

Ketone reduction

What are all are the Phase 1 Hydrolysis called?

Ester hydrolysis

Oxidation

Aromatic hydroxylation

• Recognition rule: CYP adds OH directly to the aromatic ring.

  • Even if OH were placed at another position on the aromatic ring, it would still be aromatic hydroxylation.

Aromatic hydroxylation

• CYP adds OH directly to the aromatic pyridine ring.

  • Pyridine ring: 5 carbons + 1 nitrogen

Oxidation

Benzylic hydroxylation

• Recognition rule: CYP adds OH to the first saturated carbon directly attached to an aromatic ring.

  • look for a methyl group directly attached to an aromatic ring.

Helpful side info 🙂

• Saturated carbon: C–C ✅

• Unsaturated carbon: C=C or C≡C

Benzylic hydroxylation

Oxidation

Aliphatic and alicyclic hydroxylation

• Aliphatic: Carbon is in not part of a double bond/ non-ring chain

• Alicyclic: Carbon is in a saturated, nonaromatic ring.

Recognition rule: CYP adds OH to a saturated carbon that:

• is not part of an aromatic ring

• is not part of a double bond

• is not the benzylic carbon

Aliphatic hydroxylation

Oxidation

O-dealkylation

Recognition rule: Find an oxygen with a methyl group: O–CH₃.

• CYP removes the methyl group.

• The oxygen is left as OH.

• The professor described this as removing a “mask” to expose the OH.

O-dealkylation

Oxidation

N-dealkylation

Recognition rule: Find a nitrogen with a methyl group: N–CH₃.

• CYP removes the methyl group and replaces it with H.

Sequential removal

• CYP removes only one methyl group per reaction.

• If nitrogen has two methyl groups:

  • Tertiary amine → secondary amine → primary amine

    • This requires two separate N-dealkylation reactions.

    • A methyl group automatically has the α-hydrogen needed for removal.

N-dealkylation

Reduction

Ketone reduction

Recognition rule:

• Ketone → alcohol = reduction by aldo-keto reductase

Ketone reduction

Oxidation

Alcohol and aldehyde oxidation

Starting group	What happens
Primary alcohol	Alcohol dehydrogenase (oxidizes) → aldehyde Aldehyde Aldehyde dehydrogenase (oxidizes)→ carboxylic acid
Secondary alcohol	Oxidizes to a ketone
Tertiary alcohol	Cannot oxidize further; stable

Oxidation

Explain these pathways:

⭐ Professor Example — Ibuprofen

Pathway 1

• CYP performs aliphatic hydroxylation.

• Produces a tertiary alcohol.

• Tertiary alcohol is stable → no further oxidation.

Pathway 2

• CYP performs aliphatic hydroxylation on a methyl group.

• Produces a primary alcohol.

• Primary alcohol → aldehyde → carboxylic acid.

Oxidation

Deamination

Recognition rule: Deamination removes a primary amine and produces an aldehyde.

• The aldehyde can then be converted to a carboxylic acid by aldehyde dehydrogenase.

Oxidation

Deamination - ENZYME RULE

Easy method:

1. Find nitrogen

2. Find the carbon directly beside it = α-carbon

3. Count the hydrogens on that carbon

• CH₂ = 2 α-hydrogens → MAO or CYP

• CH = 1 α-hydrogen → CYP only

Oxidation

Deamination - What happening here?

1. Phenylephrine begins with a secondary amine.

2. A secondary amine cannot be deaminated yet.

3. CYP performs N-dealkylation and removes the methyl group.

4. This produces a primary amine.

5. Its α-carbon has two α-hydrogens → MAO or CYP can deaminate it.

6. Deamination produces an aldehyde.

7. Aldehyde dehydrogenase converts the aldehyde → carboxylic acid.

• If a drug already has a primary amine, it does not need the initial N-dealkylation step.