DRUG METABOLISM

Question 1

Name the primary organ involved in drug metabolism

Answer 1

LIVER

Question 2

How many phases are there in drug metabolism?

Answer 2

2

Question 3

Describe Phase I of drug metabolism

Answer 3

Chemical modification (biotransformation) including oxidation, hydroxylation, etc. to introduce new functional group or expose a group for Phase II reactions

Question 4

Describe Phase II of drug metabolism

Answer 4

Conjugation of polar group (e.g. acetyl, sulfate, etc.) with drug

Question 5

List the CYP3A4 substrates

Answer 5

midazolam, indinavir

Question 6

List the CYP3A4 inhibitors

Answer 6

ritonavir, ketoconazole

Question 7

List the CYP3A4 inducers

Answer 7

rifampin, St. John’s Wort

Question 8

List the CYP2D6 substrates

Answer 8

codeine, fluoxetine

Question 9

List the CYP2D6 inhibitors

Answer 9

fluoxetine, quinidine

Question 10

List the CYP2D6 inducers

Answer 10

none with clinical relavence

Question 11

List the CYP2C9 substrates

Answer 11

S-warfarin, ibuprofen

Question 12

List the CYP2C9 inhibitors

Answer 12

fluconazole, amiodarone

Question 13

List the CYP2C9 inducers

Answer 13

rifampin, secobarbital

Question 14

What does the “2” denote in CYP2D6 * 1A?

Answer 14

The family

Question 15

What does the “D” denote in CYP2D6 * 1A?

Answer 15

The subfamily

Question 16

What does the “6” denote in CYP2D6 * 1A?

Answer 16

The individual gene

Question 17

What does the “1A” denote in CYP2D6 * 1A?

Answer 17

The allele

Question 18

Describe reversible CYP450 inhibition

Answer 18

Reversible inhibitors (and substrates) compete with other substrates for occupancy of active site of the same CYP enzyme similar to a receptor antagonist

Question 19

List factors that determine the binding strength of reversible CYP450 inhibition

Answer 19

• Coordination strength with heme iron
• Hydrophobic contacts with binding site of CYP
• Specific contacts (e.g. hydrogen bonds) with binding site residues

Question 20

What can reversibly inhibit CYP450?

Answer 20

A substrate
The metabolite

Question 21

When a CYP450 is reversibly inhibited, what is inhibited?

Answer 21

Sometimes the metabolism of all substrates of the CYP450, and sometimes only SPECIFIC substrates metabolism is inhibited

Question 22

Explain why an enzyme inducer may increase the metabolism of drugs metabolized by different cytochromes P450

Answer 22

Drugs bind to or induce transcription factor proteins that induce transcription of CYP genes → increased CYP450 → increased metabolism

Question 23

Explain why genetic variation in metabolism often is not the most important factor in determining variation in drug concentrations and, ultimately, clinical response

Answer 23

“For most drugs, non-genetic sources of variability are more important than genetic variation”
There are SO MANY OTHER FACTORS and genetic variation is just one