Med Chem E2

P-glycoprotein

What are xenobiotics?

Compounds foreign to the body that are not normally produced by it.

What factors make understanding drug metabolism important?

Drug exposure and dosing, route of administration, toxicities and side effects, therapeutic index, and drug hypersensitivity.

How can drug metabolism affect toxicity and side effects?

It deals therapeutic Index

What is the therapeutic index?

The range between an effective dose and a toxic dose.

What were Richard Tecwyn Williams’s major contributions?

He advanced knowledge of drug metabolism and toxicology.

What metabolic pathway concepts did Williams introduce?

Phase I and Phase II metabolic pathways.

Which drugs did Williams study the metabolism of?

Sulfonamides and thalidomide.

What is drug metabolism?

Biotransformation of pharmaceutical xenobiotics that alters their chemical structure.

Why does drug metabolism occur?

It is a defense mechanism against potentially toxic substances entering the body.

How does drug metabolism work?

it increases their polarity, which speeds elimination from the body.

How can metabolism inactivate a drug?

It affects binding to its target.

What is prodrug activation?

Metabolism converts an inactive parent drug into its active form.

What does “no effect” mean for drug metabolism?

The metabolite has similar or greater binding to the drug’s target.

Which drugs may not require metabolism before excretion?

Very polar drugs, such as tetracycline.

How are drugs that require no metabolism eliminated?

They are excreted unchanged.

What are the two major routes of metabolite elimination?

Urine and bile.

What is the primary route of drug elimination?

Urine.

How do nephrons help eliminate metabolites?

They filter certain molecules and allow others to be reabsorbed into the bloodstream.

What is the secondary route of metabolite elimination?

Bile.

How are metabolites eliminated through bile?

The liver excretes molecules with certain properties into the bile.

Are large proteins filtered by the kidneys?

No—large proteins are not filtered, only <70,000

What can happen to lipophilic compounds after filtration?

They can passively diffuse back into the bloodstream (be reabsorbed).

What happens to some polar drugs in the kidneys?

They are secreted from the bloodstream into the proximal tubule.

Which molecules are excreted in urine?

Molecules that are not reabsorbed.

What properties do drugs excreted in bile usually have?

A polar group—usually anionic, sometimes uncharged—and a molecular weight of about 500–600 or greater.

How does metabolism speed elimination of lipophilic drugs?

It converts them into more polar metabolites.

How do more polar metabolites affect kidney reabsorption?

They are less likely to be passively reabsorbed into the bloodstream after filtration.

How can metabolism reduce cellular toxicity?

Structural modification can decrease cell permeability and toxicity.

How does increased polarity affect adipose-tissue storage?

More polar metabolites are stored less in adipose tissue.

How does increased polarity from metabolism affect protein binding?

More polar metabolites bind less to plasma and tissue proteins.

What is the purpose of drug metabolism?

To convert lipophilic drugs into more polar metabolites

Why are more polar metabolites eliminated more easily?

They are more likely to be excreted in bile or secreted into the proximal tubule.

What changes make a metabolite more likely to be secreted into bile?

An increased molecular weight plus an anionic charge.

What change makes a metabolite more likely to be secreted into the proximal tubule?

An anionic charge

What anticonvulsant is an example of a drug metabolized to increase elimination?

Phenytoin.

When may metabolism be required for a drug?

When the drug must be activated before it can produce its effect.

What can drug metabolism sometimes lead to?

Some drugs can be metabolized into toxic metabolites

What toxic metabolite can acetaminophen (Tylenol) form?

N-acetyl-p-benzoquinone imine (NAPQI); problematic during a acetaminophen overdose.

What is the primary site of drug metabolism?

The liver.

Why is the liver the primary site of drug metabolism?

Blood containing food and drugs from the GI tract travels through the portal vein to the liver first.

What is the first-pass effect?

The initial metabolism or removal of xenobiotics by the liver before they reach systemic circulation.

What other sites besides the liver can metabolize drugs?

Kidneys, skin, intestinal mucosa, lungs, plasma, placenta/fetus, and the gut micro

Which enzymes help metabolize drugs in the kidneys, skin, and intestinal mucosa?

Cytochrome P450 enzymes.

Which enzyme is important for drug metabolism in the lungs?

Angiotensin-converting enzyme (ACE).

Which enzymes can metabolize drugs in plasma?

Amidases and esterases.

Can the placenta and fetus metabolize drugs?

Yes.

Can gut bacteria contribute to drug metabolism?

In the microbiome drugs can be metabolized

What is Phase I of drug metabolism?

Functionalization(activation) reactions that introduce or expose reactive or polar groups on a drug.

Which enzyme systems are involved in Phase I reactions?

Cytochrome P450 monooxygenases, flavin-containing monooxygenases, alcohol dehydrogenase, and aldehyde dehydrogenase.

What are Phase II drug metabolism reactions?

Conjugation reactions that attach activated metabolites to other molecules.

What molecules can be attached during Phase II conjugation?

Glutathione (GSH), sulfate, glycine, or glucuronic acid.

What are examples of Phase III transporters?

P-glycoprotein (P-gp), an ABC transporter, and multidrug resistance-associated proteins (MRPs).

At what point in drug metabolism can toxicity occur?

When metabolism produces a reactive electrophilic metabolite.

Which types of cells can metabolize drugs?

Hepatocytes in the liver and epithelial cells in the GI tract, lungs, kidneys, and skin.

What are the main cellular sites of drug metabolism?

Smooth endoplasmic reticulum, plasma/cellular cytoplasm, and mitochondria.

Where are soluble drug-metabolizing enzymes found?

In plasma or the cellular cytoplasm.

What are non-microsomal enzymes?

Soluble drug-metabolizing enzymes and mitochondrial metabolic enzymes.

What percentage of drug metabolism is carried out by CYP450 enzymes?

About 75%.

What do CYP450 enzymes require to function

A second protein that contributes electrons to the iron in the heme group and eventually to oxygen.

What are examples of secondary proteins used by CYP450 enzymes?

CYP450 reductase, adrenodoxin reductase, and ferredoxin reductase.

What cofactor do CYP450 enzymes contain?

A heme molecule coordinated to the sulfur of a cysteine residue.

What does the heme group allow CYP450 enzymes to do?

Activate molecular oxygen and add one oxygen atom to the drug.

What happens to the second oxygen atom from molecular oxygen during a CYP450 reaction?

It is reduced to water (H₂O).

What are cytochrome P450 (CYP450) enzymes?

The largest family of closely related enzyme isoforms that catalyze drug biotransformations; responsible for drug metabolism

in CYP3A4, what does the first number (3) represent?

The CYP family; members share more than 40% amino-acid homology.

In CYP3A4, what does the letter (A) represent?

The CYP subfamily; members share more than 55% amino-acid homology.

In CYP3A4, what does the second number (4) represent?

The gene responsible for the specific isoform.

What type of enzymes are CYP450 enzymes?

Mixed-function oxidases.

What proteins are involved in the CYP450 system?

A membrane-bound hemoprotein and a soluble flavoenzyme.

What reactions can CYP450 enzymes catalyze?

Oxidation, reduction, and hydrolysis of substrates.

What mechanism may CYP450 enzymes use?

Free-radical mechanisms.

Which CYP450 families are primarily responsible for xenobiotic metabolism?

CYP1, CYP2, and CYP3.

What do CYP450 families other than CYP1–3 mainly metabolize?

Endogenous compounds, although they can also metabolize some xenobiotics.

Why is overlapping CYP450 substrate specificity helpful?

It provides protection if one CYP450 enzyme is mutated or impaired.

What factors can cause differences in drug metabolism between patients?

Genetic factors; physiological factors such as age, gender, and intestinal flora; health status; pharmacokinetic factors; and environmental factors.

Which age groups may have especially different drug metabolism?

Children and geriatric patients.

How can intestinal flora affect drug metabolism?

It can affect enterohepatic circulation.

What patient health factors(plays a big role) can affect drug metabolism?

Nutritional status, disease state, and pregnancy.

Which disease has a major effect on drug metabolism?

Hepatic (liver) disease.

What pharmacokinetic factors affect drug metabolism?

Dose, dosing frequency, and route of administration.

How can other drugs affect drug metabolism?

They can induce or inhibit drug-metabolizing enzymes; both can lead to drug-drug interactions

What happens to CYP450 activity during induction?

CYP450 activity increases, causing increased drug clearance or bioactivation.

How can induction affect drug response?

It can increase tolerance or toxicity and decrease therapeutic effect by speeding metabolism.

What causes CYP450 enzyme induction?

Some drugs activate nuclear receptors, which increases transcription of CYP450 genes.

What is CYP450 inhibition?

One substance competitively inhibits CYP450 metabolism of another coadministered substance.

What is an example of CYP450 inhibition?

Grapefruit can inhibit CYP450 metabolism of some benzodiazepines.

What happens in Step 1 of the CYP450 reaction cycle?

The drug molecule (R–H) binds to a semi-selective hydrophobic site near the heme iron, displacing a water molecule.

What happens in Step 2 of the CYP450 reaction cycle?

CYP450 reductase reduces ferric iron (Fe³⁺) to ferrous iron (Fe²⁺).

What happens in Step 3 of the CYP450 reaction cycle?

Molecular oxygen (O₂) binds to the drug–enzyme complex.

What happens in Step 4 of the CYP450 reaction cycle?

The iron is oxidized back to Fe³⁺, and a superoxide anion is formed.

What happens in Steps 5–6 of the CYP450 reaction cycle?

Further reduction forms a peroxy intermediate.

What does the peroxy intermediate form after heterolytic cleavage?

An intermediate with highly oxidized Fe⁵⁺ iron and a highly reactive oxygen atom.

Which part of the drug does the Fe⁵⁺ intermediate usually react with?

The most electron-rich part of the drug molecule.

What happens in Step 7 of the CYP450 reaction cycle?

The oxygen atom is transferred to the activated site on the drug.

How is CYP450 reactivated for another cycle?

It releases the metabolized drug and binds a water molecule again.

What determines where CYP450 modifies a drug molecule?

The site where a free-radical intermediate can form most easily.

How do a drug’s electronic properties affect CYP450 metabolism?

Electron-withdrawing and electron-donating groups influence how easily CYP450 can remove a hydrogen.

Which radical intermediates are most stable during CYP450 metabolism?

Allylic and benzylic radicals are most stable, followed by 3° > 2° > 1° radicals.

Where do Phase I metabolic oxidations usually occur?

At activated sites on a drug molecule.

What must a carbon atom have to undergo Phase I metabolism?

A displaceable hydrogen.