lecture 22-23

Question 1

Name the primary organ involved in drug metabolism.

Answer 1

Primary- liver
Can also be metabolized in the GI tract, lungs, kidneys, brain, and the skin.

Question 2

Describe and differentiate the two phases of drug metabolism.

Answer 2

Phase I: chemical modification (biotransformation) including oxidation, hydroxylation, etc. to introduce new functional group or expose a group for phase II reactions
-typically catalyzed by P450 and CYP utilizing NADPH and oxygen

Phase II: conjugation of polar group (e.g. acetyl, sulfate, etc.) with drug

Question 3

Match the primary substrates, inhibitors, and inducers of CYP3A4, CYP2D6, and CYP2C9.

Answer 3

CYP3A4:
substrates- midazolam, indinavir
inhibitors- ritonavir, ketoconazole
inducers- rifampin, St. John’s Wort

CYP2D6:
substrates- codeine, fluoxetine
inhibitors- fluoxetine, quinidine
inducers- ?? clinical relevance

CYP2C9:
substrates- S-warfarin, ibuprofen
inhibitors- fluconazole, amiodarone
inducers- rifampin, secobarbital

Question 4

Given a specific CYP450, identify the family, subfamily, individual gene, and allelic variant component.

Answer 4

CYP2D6*1A
family: 2
subfamily: D
individual gene: 6
allele: 1A

Question 5

Differentiate between the mechanism of reversible and irreversible CYP450 inhibition.

Answer 5

reversible: reversible inhibitors and substrates compete with other substrates for occupancy of active site of the same CYP enzyme similar to a receptor antagonist
-factors that determine binding strength are coordination strength with heme iron, hydrophobic contacts with binding site of CYP, specific contacts with binding site residues
-sometimes the metabolite (not the substrate) is the inhibitor (erythromycin); might not inhibit metabolism of all substrates of specific CYP (cimetidine inhibits warfarin metabolism but not ibuprofen); competitive and different binding site moieties

irreversible: mechanism-based/suicide inhibition; metabolism of substrate generates reactive metabolite that irreversibly interacts with the heme or residues of the binding site; further metabolism of same or other drug is delayed as CYP needs to be re-synthesized

Question 6

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

Question 7

Provided a reaction, name the Phase II metabolic phase (i.e., sulfation, glucourinidation)

Question 8

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