Principles of Metabolism Handout - PDA I

What are the main consequences of drug metabolism?

It affects drug excretion, activity, and toxicity.

How does metabolism affect drug excretion?

It increases polarity (water solubility) to enhance renal and biliary excretion.

Why would lipophilic drugs accumulate without metabolism?

They are poorly excreted and remain in the body for long periods.

Does metabolism always increase water solubility?

No, some reactions like acetylation and methylation may decrease solubility.

How can metabolism affect drug activity?

Metabolites may be more active, less active, inactive, or toxic.

What is a prodrug?

An inactive drug form that is converted into an active metabolite in the body.

Why are prodrugs used?

To enhance absorption, stability, or targeted delivery.

How are many prodrugs activated?

By hydrolysis, often as ester derivatives.

Give an example of active drug → inactive metabolite

Morphine → morphine-3-glucuronide.

Give an example of active drug → more active metabolite

Morphine → morphine-6-glucuronide.

Give an example of inactive drug → active metabolite

Codeine → morphine.

Give an example of toxic metabolite formation

Acetaminophen → NAPQI.

How is acetaminophen primarily metabolized?

By sulfation and glucuronidation.

Which pathway forms the toxic metabolite of acetaminophen?

CYP-mediated oxidation.

How does NAPQI cause toxicity?

It reacts with cellular macromolecules.

What are Phase I metabolism reactions?

Non-synthetic reactions including oxidation, reduction, and hydrolysis.

What is the main goal of Phase I metabolism?

Introduce or expose functional groups on drugs.

Which Phase I reaction is most important?

Oxidation.

What enzymes catalyze Phase I oxidation?

CYP450,

FMO,

dehydrogenases,

monoamine oxidase.

What types of oxidation reactions occur?

Aromatic oxidation,

hydroxylation,

epoxidation,

dealkylation,

deamination,

desulfuration,

dehalogenation.

Why are epoxide intermediates important?

They are associated with toxicity.

What is hydroxylation?

Addition of a hydroxyl group to aliphatic side chains.

What is oxidative dealkylation?

Removal of alkyl groups from oxygen, nitrogen, or sulfur.

What is oxidative deamination?

Removal of an amine group during oxidation.

What is oxidative desulfuration?

Replacement of sulfur with oxygen.

What are reduction reactions?

Less common Phase I reactions often occurring in anaerobic environments.

Where do most reduction reactions occur?

In the large intestine via gut bacteria.

What are types of reduction reactions?

Azo, nitro, and carbonyl reductions.

What is hydrolysis?

Enzymatic breakdown of drugs using water.

Which enzymes catalyze hydrolysis?

Epoxide hydrolase,

esterase,

peptide hydrolase,

lactone hydrolase.

What are Phase II metabolism reactions?

Conjugation reactions that add endogenous molecules.

What is the purpose of Phase II metabolism?

Increase water solubility and promote excretion.

What drives Phase II reactions energetically?

High-energy bonds in the drug or conjugating molecule.

List Phase II reactions

Glucuronidation,

sulfation,

glutathione conjugation,

amino acid conjugation,

acetylation,

methylation.

Are Phase II metabolites usually active?

Usually inactive.

What is the most important organ for drug metabolism?

Liver.

What is unique about liver blood supply?

Dual supply from hepatic artery and portal vein.

What percentage of liver blood comes from portal vein?

About 75%.

What percentage comes from hepatic artery?

About 25%.

Why is portal blood important?

It contains absorbed drugs and xenobiotics from the GI tract.

What is the role of sinusoidal endothelial cells?

Allow drugs to easily access hepatocytes.

What is the role of bile in drug metabolism?

Excretion of drugs and metabolites.

Where does extrahepatic metabolism occur?

In the gastrointestinal tract.

Which cells in the intestine perform metabolism?

Enterocytes.

Where are CYP450 enzymes located intracellularly?

Endoplasmic reticulum.

What are microsomes?

ER-derived vesicles formed during cell disruption.

What does CYP450 require to function?

Oxygen and NADPH.

How is CYP450 naming determined?

Based on amino acid sequence homology.

What defines a CYP family?

Greater than 40% homology.

What defines a CYP subfamily?

Greater than 55% homology.

Which CYP families metabolize most drugs?

Families 1, 2, and 3.

Why is the liver efficient for drug metabolism?

Large size, high blood flow, and enzyme expression.

What percentage of cardiac output does the liver receive?

About 30%.

How does liver structure enhance metabolism?

Close contact between blood and hepatocytes in sinusoids.

What enzymes are abundant in liver?

CYPs, UGTs, GSTs, and others.

What are the three zones of the liver?

Zone 1, Zone 2, Zone 3.

What characterizes Zone 1?

High oxygen, low CYP450, high glutathione.

What characterizes Zone 3?

Low oxygen, high CYP450, high glucuronidation.

Where does acetaminophen toxicity occur in the liver?

Zone 3 (centrilobular necrosis).

What is the first-pass effect?

Drug metabolism in the liver before reaching systemic circulation.

What happens during first-pass metabolism?

Drug concentration is significantly reduced before systemic circulation.

Which drugs are most affected by first-pass metabolism?

High extraction ratio drugs.

Define high extraction ratio

ER > 0.7.

Define low extraction ratio

ER < 0.3.

Which CYP families are primarily involved in xenobiotic metabolism?

Families 1-3.

What is the role of CYP1 enzymes?

Metabolize planar aromatic hydrocarbons and carcinogens.

Which CYP1 enzyme metabolizes drugs?

CYP1A2.

What is the role of CYP2 family?

Largest group involved in drug metabolism.

Which CYP2 enzymes are commonly involved?

CYP2B6,

CYP2C9,

CYP2C19,

CYP2E1.

What is CYP2E1 known for?

Metabolism of alcohol and acetaminophen toxicity.

What is CYP3A4 significance?

Most abundant CYP and metabolizes ~50-60% of drugs.

What is CYP3A5?

Closely related enzyme sharing substrates with CYP3A4.

What are examples of CYP substrates?

Various drugs like warfarin, acetaminophen, and caffeine.

What is enzyme induction?

Increased enzyme activity due to repeated exposure.

How does induction occur mechanistically?

Ligand binds receptor → increases gene transcription.

What receptor is involved in CYP3A4 induction?

PXR (with RXR complex).

What is a common CYP inducer?

Rifampin.

How does ethanol affect CYP enzymes?

Induces CYP2E1.

Why is ethanol dangerous with acetaminophen?

Increases toxic metabolite formation.

What environmental factors induce CYP1A enzymes?

Smoking and charcoal-broiled foods.

What herbal product induces CYP enzymes?

St. John's Wort.

What is enzyme inhibition?

Competition between substrates for enzyme binding.

What causes inhibition?

Drugs or dietary components like grapefruit juice.

How does inhibition affect drug levels?

Increases drug concentration and risk of toxicity.

What is the main cause of drug-drug interactions?

CYP enzyme induction or inhibition.

What happens if Drug B induces metabolism of Drug A?

Drug A levels decrease.

What happens if Drug B inhibits metabolism of Drug A?

Drug A levels increase.

Which drugs are most affected by interactions?

Drugs with narrow therapeutic range.

Give examples of narrow therapeutic index drugs

Warfarin and phenytoin.