L7: General principles of drug metabolism

Question 1

What is xenobiotic metabolism?

Answer 1

The metabolism of foreign compounds in the body to facilitate elimination

Question 2

What is the aim of xenobiotic metabolism?

Answer 2

Convert lipophilic, non-endogenous compounds into polar, water-soluble products for excretion via urine or bile

Question 3

What are the sites of metabolism?

Answer 3

Liver (primary)
GI tract
kidney
skin
lungs
plasma (hydrolysis)
brain

Question 4

What are the liver functions relevant to metabolism?

Answer 4

Detoxification
macronutrient metabolism
plasma protein synthesis glycogen/vitamin/mineral storage
bile production

Question 5

What is the liver structure?

Answer 5

Made of lobules: includes portal vein, hepatic artery, bile duct, and central vein

Question 6

What are the liver cell types and their roles?

Answer 6

Hepatocytes – metabolism and biliary excretion

Cholangiocytes – bile synthesis

Kupffer cells – engulf pathogens

Stellate cells – vitamin A storage

Endothelial cells – gatekeeping

Fibroblasts – structure/repair (fibrosis)

Question 7

Can the liver regenerate?

Answer 7

Yes, via hepatocyte proliferation or liver stem/progenitor cells

No continuous regeneration: repeated damage leads to fibrosis and cirrhosis

Question 8

What are Phase I reactions?

Answer 8

Functionalisation reactions (oxidation, reduction, hydrolysis) that add/expose polar groups

Question 9

What are the main enzymes in Phase I?

Answer 9

CYP450s
oxidases
esterases
dehydrogenases
epoxide hydrolases

Question 10

What are the properties of CYP450s?

Answer 10

57 isoforms, overlapping substrates, polymorphisms (affect metabolism rates), induced/inhibited by other drugs or food

Question 11

What is the important CYP450 enzyme?

Answer 11

CYP3A4: most abundant

involved in metabolism of ~50% of drugs

Question 12

What are the inducers/inhibitors of CYP3A4?

Answer 12

St John’s Wort (induces)

grapefruit juice (inhibits)

Question 13

What are Phase II reactions?

Answer 13

Conjugation (anabolic): attaches polar groups to enhance excretion

Question 14

What are the Phase II enzyme families?

Answer 14

UGTs, SULTs, GSTs, NATs, methyltransferases, amino acid conjugators

Question 15

What is enterohepatic recirculation?

Answer 15

Drug undergoes conjugation in liver → excreted into bile → deconjugated in intestine (via β-glucuronidase) → reabsorbed into portal vein → liver/systemic circulation

Question 16

Why is enterohepatic recirculation clinically relevant?

Answer 16

Prolongs half-life, leads to persistent plasma levels

Question 17

What drugs bypass the liver initially?

Answer 17

Highly lipophilic drugs may enter lymphatic vessels before eventually reaching liver

Question 18

What are prodrugs?

Answer 18

Inactive drugs converted to active form via metabolism

Question 19

Why are prodrugs useful?

Answer 19

↑ solubility/stability, target site activation, ↓ side effects, ↑ compliance (taste, pain, stability)

Question 20

What are examples of prodrugs?

Answer 20

Heroin → morphine; Codeine → morphine (via CYP2D6); CPA → 4-OH-CPA (activated for chemotherapy)

Question 21

What is first pass metabolism?

Answer 21

Drug absorbed from GI, metabolised in liver and gut wall before reaching systemic circulation

Question 22

What are the impacts of first-pass effect?

Answer 22

Reduced oral bioavailability → requires higher oral doses

Question 23

What affects first-pass metabolism?

Answer 23

Genetic variation, blood flow variation, gut microbiota

Question 24

What are microsomal enzymes?

Answer 24

Found in smooth ER (liver)

includes CYPs

inducible by drugs (e.g. barbiturates)

Question 25

What is the microsomal fraction?

Answer 25

Pinched-off ER vesicles containing drug metabolising enzymes Isolated via homogenisation + centrifugation

Question 26

What are non-microsomal enzymes?

Answer 26

Found in cytosol/mitochondria (e.g. alcohol dehydrogenase, monoamine oxidase)

Question 27

Phase I metabolism is a ________ process that makes drugs more ____ to prepare them for ____

Answer 27

catabolic, polar, excretion

Question 28

The liver lobule consists of _______, ________, central vein, and bile ductule.

Question 29

Enterohepatic recirculation is enhanced by enzymes like _________ produced by gut microbiota.

Question 29

CYP3A4 metabolizes ~___% of drugs and is subject to ______ and ________.

Question 30

________ is an example of a prodrug converted by CYP2D6 into an active analgesic.

Question 31

Which of the following statements is TRUE regarding CYP450 enzymes? A. All CYP450 enzymes metabolize unique, non-overlapping drugs B. CYP450 enzymes are located in mitochondria C. They can be inhibited by grapefruit juice D. They are not subject to genetic variation

Answer 31

C

Question 32

Which of the following drugs is least likely to undergo enterohepatic recirculation? A. One that is lipophilic and conjugated in the liver B. A polar drug excreted via the kidneys C. A drug deconjugated by β-glucuronidase in the gut D. One reabsorbed into portal circulation

Answer 32

B

Question 33

A patient taking a medication metabolised by CYP3A4 drinks grapefruit juice daily. What is the most likely outcome? A. No change in drug effect B. Increased drug metabolism C. Reduced plasma concentration D. Increased drug toxicity

Answer 33

D

Question 34

What is the primary purpose of phase II metabolism? A. Making drugs more lipophilic B. Conjugating drugs for easier excretion C. Reducing half-life D. Preventing renal filtration

Answer 34

B

Question 35

Prodrugs are designed to: A. Be excreted faster B. Evade metabolism C. Enhance taste, reduce irritation, and improve absorption D. Remain inactive in the body

Answer 35

C