Drug Metabolism

Question 1

True or false: lipophilic compounds are efficiently eliminated from the body.

Answer 1

False; this is why lipophilic compounds can accumulate in adipose tissue and membranes, and why they are poorly excreted in the urine.

Question 2

True or false: most drugs are lipophilic and readily reabsorbed in the kidney.

Answer 2

True! Unbound drug molecules are filtered through the glomerulus and readily reabsorbed in the kidney tubules under the influence of pH and urine flow rate.

Question 3

Why does the fact that most drugs are lipophilic contribute to drug accumulation and toxicity in the body?

Answer 3

Lipid-soluble drugs are readily reabsorbed in the kidney tubules, causing a higher concentration in the systemic circulation and resulting drug accumulation/toxicity.

Question 4

What is drug metabolism?

Answer 4

the enzymatically catalyzed conversion of a drug or xenobiotic compound to its metabolites

Question 5

What are the primary roles of drug metabolism?

Answer 5

• to inactive and detoxify pharmacologically active drugs and xenobiotics
• to enhance drug excretion/elimination

Question 6

What is the one situation in which drug metabolism activates drug compounds instead of inactivating them?

Answer 6

when prodrugs are administered

Question 7

What are examples of prodrugs discussed in class?

Answer 7

Irinotecan –> SN-38

others include clopidrogel, codeine, prednisone, levodopa, and captopril

Question 8

What is the major site of drug metabolism? Which organ plays a secondary role?

Answer 8

• liver=main site

- intestine also plays a significant role

Question 9

True or false: drug metabolism enzymes are only expressed in certain cells, like hepatocytes.

Answer 9

False- drug metabolism enzymes are expressed in essentially ALL cells.

Question 10

What are the major subcellular sites of drug metabolism?

Answer 10

• ER (CYP450 and others, like glucuronosyltransferase)

- cytoplasm (most other metabolic enzymes)

Question 11

When does a drug have 100% bioavailability?

Answer 11

when it is injected intravenously

Question 12

Provide an example of a drug-conjugate that is NOT inactive.

Answer 12

morphine (when it undergoes phase II reactions, it is not inactivated, but converted to the more active morphine-6G form)

Question 13

Besides the liver and intestine, where can drugs be metabolized?

Answer 13

skin, kidney, lungs, brain

Question 14

What are the major enzymes involved with Phase I rxns?

Answer 14

cytochrome P450 enzymes (CYP450)

• specifically catalyze oxidation rxns
• account for 75% of all phase I rxns

Question 15

CYP450 rxns require:

Answer 15

• drug substrate
• molecular oxygen
• NADPH
• NADPH-CYP450 oxidoreductase

Question 16

Which CYP enzyme represents 30% of all CYP450 enzymes in the liver and accounts for the metabolism of >50% of clinically used drugs?

Answer 16

CYP3A4

Question 17

CYP450 superfamily enzymes are expressed at highest levels where in the body?

Answer 17

liver and GI tract

Question 18

Most active enzymes for drug metabolism are which subfamilies?

Answer 18

CYP2C, CYP2D, and CYP3A

Question 19

Subcellularly, where do most phase II rxns occur? What is the exception?

Answer 19

cytoplasm- exception is glucuronidation, which occurs on ER membrane

Question 20

Which drugs are direct targets for phase II metabolism because they already contain small polar functional groups?

Answer 20

morphine and isoniazid

Question 21

What is the most frequent and important of all phase II rxns? What is this rxn catalyzed by?

Answer 21

glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT)

Question 22

When/why are prodrugs given?

Answer 22

when the prodrug has a better pharmacokinetic profile than its active metabolite (solubility, absorption, distribution, stability, toxicity, etc.)

Question 23

Which organ accounts for the excretion of MOST drugs?

Answer 23

kidney

Question 24

What happens to drugs that are recirculated via enterohepatic circulation?

Answer 24

these drugs are actively transported into the bile and stored in the gallbladder before release into GI tract (and ultimately excreted in feces); enterohepatic recirculation can significantly prolong the pharmacological effect of drugs

Question 25

How does grapefruit juice affect metabolism of certain drugs?

Answer 25

Grapefruit juices increases oral bioavailability of CYP-3A4-metabolized drugs (compounds in grapefruit juice inhibit CYP3A4 activity, thereby decreasing 3A4 metabolism of drug in the GI tract–> more drug reaches liver and systemic circ–> potential for increased therapeutic effect–> also potential for adverse effects)

Question 26

How does CYP3A4 affect drug bioavailability?

Answer 26

It is expressed in the GI tract and metabolizes drugs during the absorption processes, thus decreasing F (part of first pass effect)

Question 27

Why is a dose reduction necessary in the elderly?

Answer 27

due to decreased activity of phase I enzymes/metabolism

Question 28

What is pharmacokinetic tolerance? Provide an example of a drug that displays this.

Answer 28

It describes the phenomenon by which some drugs induce the enzyme responsible for their own metabolism, reducing levels of active drug over time.
*Ex: carbamazepine

Question 29

What are the major features of phase I vs. phase II metabolic drug reactions?

Answer 29

• phase I: oxidation, reduction, hydrolysis

- phase II: conjugation

Question 30

What are the 2 principal mechanisms underlying metabolic drug-drug interactions?

Answer 30

• induction of metabolic enzymes

- inhibition of metabolic enzymes

Question 31

What are some well-known inhibitors of CYP450 isozymes?

Answer 31

ritonavir, grapefruit juice, fluconazole, ketoconazole, itranaconazole, omeprazole, erythromycin, clarithromycin

Question 32

What are some well-known inducers of CYP450 isozymes?

Answer 32

St. John’s wort, rifampin, glucocorticoids, carbamazepine, phenobarbital, phenytoin, pioglitazone
(St. John Rides in a Green Car to the Party, Pool, and Picnic)

Question 33

How do rifampin and ritonavir differentially affect cyclosporin metabolism?

Answer 33

• rifampin: 3A4 inducer; increases metabolism of cyclosporin, thereby increasing risk of organ rejection
• ritonavir: 3A4 inhibitor; decreases metabolism of cyclosporin, thereby increasing risk for nephrotoxicity

Question 34

What are the principal factors known to influence drug metabolism?

Answer 34

• age
• pregnancy
• diet and envt.
• disease
• metabolic drug interactions
• interactions b/t drugs and endogenous compounds
• genetics

Question 35

What leads to gray baby syndrome?

Answer 35

Infants inherently have a deficiency in conjugating phase II enzymes. When they are given chloramphenicol (used for treatment of bacterial infections), they get a buildup of a phase I metabolite, resulting in circulatory collapse and cyanosis.

Question 36

How do inflammatory cytokines affect CYP450 isoforms?

Answer 36

decrease expression of many isoforms

Question 37

How does cigarette smoke affect drug metabolism?

Answer 37

Chemicals in cigarette smoke induce CYP1A2 3-fold, which may cause smokers to require higher doses of drugs metabolized by CYP1A2.