GP 13 - Pharmacokinetics 2

Question 1

What are the two primary processes by which drugs are eliminated from the body?

Answer 1

• Excretion (primary)
• Metabolism (secondary)

Question 2

What are the 4 ways metabolism can biotransform a drug?

Answer 2

1. Convert an active drug into an inactive drug
2. Convert an unexcretable drug into an excretable metabolite
3. Convert an active drug into an active/toxic metabolite
4. Convert an inactive prodrug into an active drug

Question 3

Describe the two kinds of biochemical reactions involved in drug metabolism.

Answer 3

Phase I - oxidations, reductions, decarboxylations, deaminations, and hydrolytic reactions. These reactions usually serve to convert an active drug into a more polar metabolite. In some instances, activity is only modified or even enhanced.

Phase II - conjugation reactions forming a covalent bond between the drug and glucuronate, acetate, glutathione, amino acids, or sulfate

These two phases often occur sequentially

Question 4

How are prodrugs often activated? What prime example of this was given in class?

Answer 4

By a phase I reaction hydrolyzing an ester or amide linkage present in the prodrug.

Example - cyclophosphamide being converted to an active anticancer metabolite

Question 5

List the tissues, besides the liver, that participate in drug metabolism.

Answer 5

All tissues are capable of drug metabolism to some degree but particularly active sites are:

• GIT
• Kidneys
• Skin
• Lungs

Question 6

Where in the cell do phase I and phase II reactions normally occur?

Answer 6

Phase I reactions typically occur in the ER

Phase II reactions typically occur in the cytosol

Question 7

How are the Human P450 families categorized? Which category is the largest and which one metabolizes the most drugs?

Answer 7

Humans have 18 families of P450 genes which are divided into 43 subfamilies.

The CYP3A4 isoform accounts for 30% of the P450 enzymes in the liver and it metabolizes about 50% of all drugs

Question 8

Describe how P450 induction occurs. What examples of this were given in class?

Answer 8

P450 enzyme induction typically occurs by a drug binding to a xenobiotic receptor in a hepatocyte, thereby activating it, and causing it to translocate into the nucleus and bind to the promoters of various P450 isoforms, increasing their transcription.

Examples - phenobarbital, rifambin, and carbamazepine increase the synthesis of one or more P450 isoforms

Question 9

What are the major clinical consequences of P450 induction? What examples of this were given in class?

Answer 9

• A drug can increase its own metabolism
• A drug can increase the metabolism of a coadministered drug
• Induction of P450s can also result in the production of toxic levels of reactive drug metabolites, resulting in tissue damage

Example - St. John’s Wort induces CYP3A4 and is often coadministered wih drugs to reduce their concentration

Question 10

What are the primary examples of drugs that inhibit P450s?

Answer 10

• Amiodarone
• Cimetidine
• Ketoconazole
• Macrolide Antibiotics - erythromycin & clarithromycin
• Chloramphenicol
• Grapefruit Juice

Question 11

Which drug examples given in class inhibit P-glycoprotein?

Answer 11

The macrolide antibiotics - erythromycin & clarithromycin

Question 12

Describe the example of toxic metabolism given in class? What is the antidote to this toxicity?

Answer 12

Acetaminophen (Tylenol) is metabolized into three different metabolites, twoof which are harmless and easily exreted in the urine. One of the metabolites, NAPQI, is further metabolized into two metabolites. One of them is also harmless and easily excreted in the urine but the other causes cell death. Normally this toxic metabolites is created in such small quantities that the liver can detoxify it immediately. However, an acetaminophen OD can cause toxicity.

This is treated with N-acetylcysteine which reacts with NAPQI

Question 13

List the primary genetic variations that influence pharmacotherapy. Which one is the most common?

Answer 13

• Variation in drug metabolism/transport proteins
• Variation in the targets/pathways of drugs
• Variation associated with idiosyncratic drug effects

The most common one is genetic variation in enzymes that catalyze drug metabolism

Question 14

What two foods have important pharmacokinetic altering properties? What are those properties?

Answer 14

• In the small intestine, grapefruit juice inhibits both CYP3A4 and P-glycoprotein
• Charcoal-broiled foods and cruciferous vegetables (e.g. - cauliflower, cabbage, broccoli, brussel sprouts) induce CYP1A enzymes

Question 15

What environmental factors affect pharmacokinetics?

Answer 15

• Aromatic hydrocarbons in cigarette smoke cause AhR-mediated P450 enzyme induction
• Workers exposed to some pesticides metabolize certain drugs more rapidly

Question 16

How does age affect pharmacokinetics?

Answer 16

Many reactions of biotransformation are slowed in both young children and the elderly

Question 17

What are the most common modes of drug excretion?

Answer 17

Urine (most common)

Bile (only a select few drugs)

Question 18

Describe the key steps to renal excretion of drugs and the factors that affect each step.

Answer 18

1. Glomerular Filtration - only affected by size of drug, need to have a MW <20,000
2. Active tubular secretion in the proximal tubule by two active transport systems, one for anions and one for cations - nonpolar drugs won’t be secreted
3. Passive reabsorption of liposoluble drugs - dependent on drug charge which is often dependent on filtrate pH

Question 19

T/F - drugs secreted from the liver in the bile will be excreted in the feces

Answer 19

Mostly False

More commonly they are reabsorbed into the blood and ultimately excreted in the urin. Some will make out in the feces, though.