Module 6 Drug Discovery

Question 1

Abacavir (Ziagen)

Answer 1

• Should be avoided in patients with HLA-B* 5701 allele, unless benefits outweighs risks
• Clinical Effect : Increased risk of hypersensitivity reactions

Question 2

Carbamazepine (Tegretol)

Answer 2

• Should be avoided in HLA-B*1502, unless potential benefit outweighs risks.
• The HLA-B*1502 allele increases the risk for serious and potentially fatal dermatologic reactions (e.g., Stevens- Johnson syndrome and toxic epidermal necrosis) with carbamazepine.

Question 3

Irinotecan (Camptosar)

Answer 3

• The UGT1A1*28 allele is associated with increased risk for irinotecan-induced neutropenia, with homozygotes having the highest risk.
• Lower irinotecan starting doses are indicated in patients known to be homozygous for the UGT1A*28 allele.
• Patients with UGT1A1 deficiency are at an increased risk of developing severe toxicities including gastrointestinal toxicities and neutropenia

Question 4

Celecoxib

Answer 4

Celecoxib clearance is reduced in carriers of the CYP2C9*3 allele. Celecoxib should be administered with caution and at lower doses in patients with the CYP2C9*3 allele.

Question 5

Warfarin

Answer 5

• The CYP2C9*2 and *3 alleles are associated with reduced warfarin metabolism and increased bleeding risk, while the VKORC1-1639A allele is associated with increased warfarin sensitivity.
• Lower doses of warfarin should be started in patients known to have reduced function CYP2C9 or VKORC1 alleles. However, genetic testing is not mandated.

Question 6

Trastuzumab (Herceptin)

Answer 6

• Decreased tumor progression in breast cancer with trastuzumab has only been demonstrated when HER2 is overexpressed.
• Overexpression of HER2 should be confirmed by protein overexpression or gene amplification prior to trastuzumab initiation.

Question 7

Antidepressants

Antipsychotics

Antiarrhythmics

Atomoxetine

(Strattera)

Answer 7

• CYP2D6
• Greater likelihood of adverse reactions in people who are poor metabolizers; greater likelihood of treatment failure in people who are rapid metabolizers

Question 8

Codeine

Answer 8

• CYP2D6
• Greater likelihood of adverse reactions in people who are rapid metabolizers; greater likelihood of treatment failure in people who are slow metabolizers

Question 9

Beta-blockers (ends with -lol)

Answer 9

• CYP2D6
• Marked differences in plasma levels reported; clinical significance not currently known

Question 10

Warfarin

Tolbutamide (Orinase)

Glipizide (Glucotrol)

Phenytoin (Dilantin)

Answer 10

• CYP2C9
• Poor metabolizers may exhibit toxic drug effects

Question 11

Proton pump inhibitors (Omeprazole, Pantoprazole)

Answer 11

• CYP2C19
• Marked differences in plasma levels reported; increased gastric and duodenal ulcer healing rates documented in poor metabolizers and decreased rates in ultra-rapid metabolizers

Question 12

Fluorouracil

Capecitabine

(Xeloda)

Answer 12

• Dihydropyridine dehydrogenase (DPD)
• Patients with DPD deficiency experience profound toxicity effects including lifethreatening gastrointestinal

toxicity, myelosuppression, and neurological toxicities

Question 13

Mercaptopurine (Purinethol)

Thioguanine (Tabloid)

Azathioprine (Imuran)

Answer 13

• Thiopurine methyltransferase (TPMT)
• Patients with TPMT deficiency experience profound myelosuppression with normal doses

Question 14

Oral Contraceptives

Tamoxifen (Nolvadex)

Answer 14

• Factor-V Leiden
• Increased incidence of deep vein and cerebral vein thrombosis (Tamoxifen included based on preliminary evidence)

Question 15

Allopurinol (Xyloprim)

Answer 15

• HLA-B*5801
• Increased risk for hypersensitivity with this variant.

Question 16

OATP & P-Glycoprotein transporters mediate the cellular uptake and excretion of ___

Answer 16

• Fexofenadine & Digoxin
• NSAID’s
• HIV-Protease inhibitors
• Beta-Lactam Antibiotics

Question 17

The ACE inhibitor-induced cough has been linked to a polymorphism of which gene?

Answer 17

Bradykinin

Question 18

Resources for Pharmacogenetic Info

Answer 18

• FDA
• PharmGKB
• Genetics/Genomics Competency Center

Question 19

Pharmacogenomics can be used in drug discovery and development to

Answer 19

• Maximize the likelihood of high efficacy and low toxicity of the drug
• Increase the likelihood of a new drug making it to market quickly, safely , and with maximal benefits

Question 20

Imatinib

(Gleevec)

Answer 20

• bcr-abl tyrosine kinase
• Administration to patients with chronic myeloid leukemia results in decreased proliferation and survival of leukemia cells

Question 21

Imatinib mesylate

Answer 21

• CD117
• Gastrointestinal stromal tumor cells possessing the CD117 (or c-Kit) mutation have shown regression with imatinib, and imatinib is indicated for patients with the CD117 mutation and unresectable or metastatic gastrointestinal stromal tumors.

Question 22

Hydralazine, Isoniazid, procainamide

Answer 22

• N-acetyltransferase 2 (NAT)
• Increased susceptibility to adverse effects of drugs that are acetylated. – fast acelylators may not respond to these drugs
• Slow acetylators experience toxicity

Question 23

Phase 1 metabolizing enzymes

Answer 23

CYP families

DPD - (5FU, xeloda)

FMO

Question 24

Phase 2 metabolizing enzymes

Answer 24

• N-acetyltransferase 2 (NAT 2) : Hydralazine, Isoniazid, procainamide
• Uridine diphosphateglucuronosyltransferase: (UGT) Irinotecan
• Thiopurine S-methyltransferase (TPMT) : Mercaptopurine, Azathioprine
• Catechol O-methyltransferase (COMT): Levodopa