Drug Biostransformation

Question 1

Besides catalyzing reactions what are enzymes also responsible for?

Answer 1

Metabolism (biotransformation) of compounds foreign to the body

Question 2

What are the two primary ways in which drugs are eliminated from the body?

Answer 2

1. They may be excreted in the urine or feces (unchanged)

2. Are metabolized or biotransformed and then excreted

Question 3

What is the major objective of drug bitransformation?

Answer 3

To make nonpolar (hydrophobic) drugs more polar so that they can be more readily excreted

Question 4

What happens to a compound that is biotransformed by body enzymes?

Answer 4

It typically becomes less active or inactive compared to the parent drug

Question 5

What can biotransformation cause a drug to do

Answer 5

Cause it to no longer have a therapeutic effect or it can activate it (prodrug)

Question 6

What is a prodrug?

Answer 6

A drug that must be biotransformed in order to have a therapeutic response

Question 7

Where do most biotransformation reactions occur?

Answer 7

in the liver; but some in kidneys GI tract, skin and lungs

Question 8

What is the path of a drug when it is taken orally?

Answer 8

Absorbed first in the GI tract to enter the bloodstream. Once in bloodstream, these drugs are transported directly to the liver thro the hepatic portal vein, then out to systemic circulation

Question 9

What is the case of how much drug reaches the body when it goes thro the liver first?

Answer 9

Most of the drug is biotransformed and metabolized prior to reaching the systemic circulation

Question 10

What is the “first pass effect”

Answer 10

Refers to the amount of drug that is removed by liver before it reaches the blood

Question 11

What are the most important enzymes for drug metabolism and where are they located?

Answer 11

Cytochrome P450 Monooxygenases which are in high concentrations in the liver
Responsible for majority of all drug biotransformations

Question 12

What do the cytochrome P450 enzymes contain?

Answer 12

Heme-containing membrane proteins that are capable of catalyzing a variety of Phase 1 reactions

Question 13

How many Cytochrome P-450s are there in humans?

Answer 13

about 50

A number of them are only used in metabolism of xenobiotics (drugs) / also involved in drug-drug interactions

Question 14

What are the two process that result from CYP 450 interactions?

Answer 14

Inhibition and induction

Question 15

What is an inhibition interaction for CYP 450?

Answer 15

Competitive binding at an enzymes bind site

making the rxn happen less often (inhibits)

Question 16

What is an induction interaction for CYP 450?

Answer 16

A substance (the drug) stimulates the synthesis of an enzyme or reduces its degradation (breaking it down) and the metabolic capacity for the isozyme is increased

Question 17

What are prodrugs designed?

Answer 17

They take advantage of absorption or metabolic properties to provide more optimal drug therapy

Question 18

What is a prodrug that is activated after taken orally?

Answer 18

Plavix by CYP2C19

Question 19

What are the two types of biotransformation reactions?

Answer 19

Phase I

Phase II

Question 20

What are phase I reactions?

Answer 20

Functionalization reactions: They induce or expose a functional group on a compound; usually these result in a loss of activity, but in some cases it can enhance or retain activity

Question 21

What are phase II reactions?

Answer 21

biosynthetic reactions that result in a covalent linkage between a function group on the parent drug to a highly polar conjugate.

Question 22

What is N-dealkylation?

Answer 22

Phase I oxidative reaction

Separate RNHCH3 to RNH2+CH2O

Question 23

What is O-dealkylation?

Answer 23

Phase I oxidative reaction

separate ROCH3 to ROH +CH20

Question 24

What is aliphatic hydroxylation?

Answer 24

Phase I oxidative reaction

Adds an alcohol to a carbon

Question 25

What is an aromatic hydroxylation?

Answer 25

Phase I oxidative reaction

Adds and alcohol to a phenyl group

Question 26

what is an N-Oxidation?

Answer 26

Phase I oxidative reaction

Adds and alcohol to an amine

Question 27

What is an S-oxidation?

Answer 27

Phase I oxidative reaction

Adds an oxygen double bond to Sulfur

Question 28

What is deamination?

Answer 28

Phase I oxidative reaction

Adds a double bond oxygen to make a double bond and an amine

Question 29

What is are hydrolysis reactions

Answer 29

Phase I oxidative reaction
Create a carboxyclic acid and and alcohol
(can do the same with a to create carboxcylic acid and an amine)

Question 30

What do phase II reactions do to compounds?

Answer 30

make them more hydrophilic by covalently linking them to a polar compound such as glucuronic acid, sulfate, glutathione, amino acids or acetate

Question 31

What is Enterohepatic re-circulation?

Answer 31

A glutathione conjugation produces a high molecular weight conjugate which is excreted in the bile.
This leads to enzymatic cleavage and the release and re-absorption of the drug back into the system circulation.

Question 32

What is glutathione (GSH)

Answer 32

a tripeptide found in most tissues (most kidney and liver)

helps with detoxification of many drugs tho phase II conjugation rxns.

Question 33

What happens when acetaminophen is taken at high doses?

Answer 33

It is toxic to the liver. At high doses there is greater production of metabolites which are normally minor. the NAPQI interacts with cellular proteins and when NAPQI is in excess it depletes cellular stores of glutathione
This is what causes it to be toxic