Drug Metabolism

Question 1

What is the biochemical idea behind biotransfromation/ what is the ultimate goal?

Answer 1

Converting lipophilic drugs to more hydrophilic compounds to facilitate their EXCRETION from the body.

Question 2

Xenobiotics

Answer 2

Drug or non-essential exogenous compound

e.g. drug, toxin, food additive, environmental chemical, insecticide, herbicide, etc.

Question 3

Where does metabolism primarily take place, be specific.

Answer 3

Smooth endoplasmic reticulum of liver cells (high concentration of drug metabolizing enzymes)

Question 4

Oral bioavailability

Answer 4

fraction of total dose that reaches systemic circulation

Question 5

Phase I chemical modifications

Answer 5

Reduction
Oxidation (w/ or w/out CYP mediation)
Hydroxylation
Hydration

Question 6

Phase II modifications

Answer 6

Conjugation of polar groups:

• Acetylation
• Amino acid (especially polar ones)
• Glucuronidation
• Glutathione
• Methylation
• Sulfation

Question 7

What is the difference between phase 0 and phase III?

Answer 7

0- protein pumps that pump chemicals into system

III- pumps drugs out of cell

Question 8

What is the #1 route of elimination of most drugs?

Answer 8

Metabolism

Question 9

Roughly how many drugs are metabolized by CYP? (%)

Answer 9

75%

Question 10

What are the top three most frequently used CYPs?

Answer 10

1) CYP3A (1/3 of all drugs)
2) CYP2C9
3) CYP2D6 (1/5 of all drugs)

Question 11

Prodrug

Answer 11

Drug metabolite(s) may be more active than the parent compound or the parent compound may require activation for biological activity => bioactivation

Question 12

__ is the prodrug of endoxifen.

Answer 12

Tamoxifen

Endoxifen is 30-100 times more potent.

Question 13

Compound from grill smoke :(

Answer 13

Benzoapyrene

Question 14

Name 5 significant points about idiosyncratic drug metabolism.

Answer 14

1) DILI! - drug induced liver injury
2) DILI- induced acute liver failure –> death or transplant
3) Hypersensitivity
4) #1 reason new therapeutic agents not approved by FDA
5) #1 reason for withdrawal from market

Question 15

What is GWAS?

Answer 15

Genome wide association study: each dot represents a polymorphism. Studying susceptibility to adverse drug effects by genes.

Question 16

What are the other substrates of CYP oxidation reactions (besides the drug)?

Answer 16

NADPH and oxygen

Question 17

The active site of CYP contains an ___.

Answer 17

Iron-heme cofactor

-Iron is coordinated to four nitrogen atoms of the heme, to one thiolate, and a water molecule (in the native state)

Question 18

Probably look at cytochrome P450 reaction.. along with other reactions.

Answer 18

:)

Question 19

Which CYP is notably inducible by smoking?

Answer 19

CYP1A1/2

Question 20

CYP1A family metabolizes __, __, and, __.

Answer 20

Polyaromatic hydrocarbons (PAH), arylamines, nitrosamines

Question 21

Liu insisted on remembering this particular (drug) inhibitor of CYP3A4…

Answer 21

ketoconazole

Question 22

Two most typical actions of phase II reactions?

Answer 22

Bio-inactivation and detoxification

Question 23

___ are the most dominant phase II enzymes.

Answer 23

UDP-glucuronosyl transferases

Question 24

Why are UGTs so dominant?

Answer 24

• Readily available supply of glucose and uridine triphosphate in liver: UDPGA is product of four different enzymatic reactions
• Many functional groups can form glucuronide conjugates

Question 25

Where are UGT and P450 located?

Answer 25

Co-localized on endoplasmic reticulum