Exam 1 - ch. 4 review

Question 1

Describe drug biotransformation and the difference between a prodrug and an active
drug.

Answer 1

Biotransformation is the act of changing/modifying the drug once it’s in the body. It can activate it or inactive it (metabolize). primarily in the liver.

Prodrug is inactive or weakly active that undergoes biotransformation to become active.

Active drugs are active when you take them then become inactive throughout biotransformation to be inactivated/excreted.

Question 2

Describe the first pass effect, and the route of blood through the liver.

Answer 2

Everything we swallow goes through the first pass effect before it hits the bloodstream.

Oral: GI -> local veins -> hepatic portal vein -> SINUSOIDS -> hepatic vein -> vena cava -> systemic circulation

Question 3

Route IV drug takes through liver

Answer 3

Systemic circulation -> hepatic artery -> sinusoids -> hepatic vein -> vena cava -> systemic circulation

Question 4

Where are drugs specifically biotransformed in the liver? what is the term he used for them?

Answer 4

Sinusoids, they are very leaky.

Question 5

What do phase I reactions do and what are the the major phase I metabolic reactions?

Answer 5

Vast majority of drugs. Convert drug to more polar metabolite, taking them from lipophilic to hydrophilic to be excreted, by adding or unadding function group.

Oxidation, reduction, dehydrogenation, hydrolysis.

Question 6

Oxidation reaction

Answer 6

Phase I. involves a loss of electrons, CYP450 is this reaction, converting molecule to more polar metabolite

Question 7

Reduction reaction

Answer 7

Phase I. This is the process of gaining electrons.

Question 8

Dehydrogenation

Answer 8

Phase I: Remove OH group

Question 9

Hydrolysis

Answer 9

Phase I: breaks bonds

Question 10

List the major phase II metabolic reactions.

Answer 10

Glucoronidation, acetylation, glutathione conjugation, glycine conjugation, sulfation, methylation, water conjugation.

Question 11

Glucoronidation

Answer 11

UGTs, add glucuronic acid to phenols, alcohols, carboxyl, and sulfhydryl groups. primarily in liver.

Question 12

Glutathione-S-transferase

Answer 12

GST: high in RBCs, ubiquitous, increases water solubility.

Question 13

Know which P450 isoforms are
responsible for the greatest number of important reactions.

Answer 13

2B6: 8%

2D6: 20%

3A4¹: 50%, which is 30% of all drugs that undergo phase 1 reactions.

Question 14

Delineate the generic pathway of Cyp450 metabolism

Answer 14

Lipophilic drug binds to CYP450 enzyme, ferric (Fe³⁺ reduces to ferrous state (fe²⁺) by an electron from NADPH-P450 reductase. The iron then binds to O₂, becoming P450[Fe²⁺-O₂]. The O₂ undergoes protonization and leads to one oxygen becoming H₂O and the other incorporated into drug, forming a hydroxyl (-OH) group, now hydrophilic and dissociate from CYP450 to be excreted.

NADPH also becomes NADP+

Question 15

Define what is meant by “wild type” CYP enzymes, and how they are notated.

Answer 15

*1 is the wild type, and that means it’s the most common variation in population.

Question 16

Predict the effect of a drug based on enzyme induction or inhibition with a second drug.

Answer 16

Induction: decreases drug effect IF metabolism deactivates the drug. INCREASES drug effect if metabolism activates the drug.

Question 17

Drug 1 is metabolized by CYP3A4 to be inactive, and drug 2 is an inducer of CYP3A4. What happens to drug 1?

Answer 17

Become less effective and metabolized faster.

Question 18

Prodrug is activated by CYP3A4, and drug 2 is an inducer of CYP3a4. what happens to prodrug?

Answer 18

Becomes more effective, could achieve toxicity faster.

Question 19

Drug1 is inactivated by CYP3A4, which drug 4 inhibits. What happens to drug 1?

Answer 19

Does not become inactivated nearly as fast, leads to toxicity.

Question 20

Prodrug is activated by CYP3A4, and Drug 4 is an inhibitor of that. What happens to prodrug?

Answer 20

Doesnt get activated, desired effect not achieved.

Question 21

Describe the pathways by which acetaminophen is metabolized (1) to harmless products
if normal doses are taken and (2) to hepatotoxic products if an overdose is taken

Answer 21

Normal: tylenol undergoes sulfation and glucuronidation (phase 2 reactions). Sulfation turns it into nontoxic sulfate, and glucuronidation turns its into nontoxic glucuronide.

Toxic: CYP2E1 and CYP3A4 (phase 1 reeactions) break it down to assist the liver in the toxic levels. Turns into GSH-Conjugation, and eventually Mercapturic acid conjugate which is a toxic byproduct.

Question 22

List additional factors affecting drug metabolism

Answer 22

Diet, environment (cigs), age (pre vs post pubescent), sex (males metabolize faster in rats), disease state such as fat, hepatitis, cirrhosis, liver CA, cardiac disease. and lastly genetics.