Pharmacogenomics

Question 1

Pharmacogenomics

Answer 1

. Study of how individual’s genetic makeup affects their body’s response to drugs

Question 2

Amplichip from Roche

Answer 2

. Tests forpolymorphism in CYP2D6 and CYP2C19
. Used to confirm AFTER treatment failure or adverse rxn to a drug
. First FDA-cleared test, physician prescribed
. Over 99% accuracy
. CYP2D6 tests up to 33 alleles
.CYP2C19 tests for 3 alleles

Question 3

HIV gene testing

Answer 3

. Tests for characteristics of viral infectious agent to better determine treatment (not for characteristics of patient)
. Several tests available (TRUGENE, Virgo-seq HIV-1)

Question 4

UTG1A1 molecular assay

Answer 4

. Tests for polymorphism in UDP-glucuronosyltransferase A1A (coded by gene UGT1A1)
. Involved in metabolism for endogenous compounds and drugs
. Enzyme adds glucuronic acid to substrate
. Application primarily in cancer chemotherapy
. Identifies individuals at risk for severe toxicity (neutropenia) when treated w/ irinotecan

Question 5

Mamma print (agendia)

Answer 5

. Assesses risk for breast cancer to spread to other parts of body
. Tests 70 genes related to metastasis
. Tissue sample of tumor tested

Question 6

Oncotype DX (Genomic health)

Answer 6

. Assesses if it would be helpful to add chemo to hormonal treatment
. Used only in estrogen receptor positive tumors that are stage I or II and lymph node negative

Question 7

Cytochrome p450

Answer 7

. Major way to modify and excrete drugs, named for heme group bounty active site and absorbs light at 450 Nm
. 150 different genes coding for 150 different proteins
. Genetic variation btw people exists
. All catalyze addition of hydroxyl group to hydrophobic substrate to make product more water-soluble for excretion
. Located in liver mostly, and in adrenals, ovaries, testes, and any organs where steroid hormones are synthesized/degraded

Question 8

Induction

Answer 8

Make more copies of a protein
. Results in inc. biological function of that protein
. Causes loss of therapeutic effect of drug B

Question 9

Drugs that inhibit cytochrome p450 enzymes cause ____

Answer 9

Inc. therapeutic effect or inc. adverse side effects

. Important for multiple drug interactions

Question 10

Foods known to affect Cytochrome p450 (CYP) metabolism

Answer 10

. Broccoli and Brussels sprouts induce CYP1A2
. Char-grilled meat induces CYP1A2
. Ethanol induces CYP2E1
. Grapefruit juice moderately inhibits CYP3A4,5,7 (2-fold inc. in levels of drug or 50-80% dec. in clearance)
. Starfruit inhibits CYP 3A4,5,7
. Coffee: metabolized by several cytochrome p450 drugs

Question 11

Dietary supplements afftincg CYP metabolism

Answer 11

. St. John’s wort induces CYP3A,4,5,7

Question 12

Smoking tobacco induces _______

Answer 12

CYP1A2

Question 13

Gastric ulcers

Answer 13

. Sores on lining of stomach or duodenum
. 10% of Americans develop these sometimes in lifetime
. Cause: infection w/ H. Pylori, long-term use of NSAIDs, cancerous tumors of stomach or pancreas

Question 14

Gastric ulcer treatment

Answer 14

. Antibiotics
. Drugs that reduce stomach acid (H2 blockers, proton pump inhibitors)
. Drugs to protect stomach lining

Question 15

Lansoprazole

Answer 15

. Proton pump inhibitor
. Favored treatment H. Pylori peptic ulcers
. Metabolized by hepatic CYP2C19
. Treatment more effective w/ people w/ mutant variants of CYP2C19 2 and 3 alleles assoc. w/ truncated and inactive enzyme bc it is unable to bind to heme
. Wildtype patients: 80.2% success
. Wt/my: 97.8% effectiveness
. Mt/mt: 100% success

Question 16

Codeine

Answer 16

. Inactive until converted into morphine by CYP2D6
. People who are poor metabolizers will have dec. effectiveness and no pain relief
. Ultra rapid metabolizers are also a problem bc morphine production is too high then

Question 17

CYP2D6

Answer 17

. Small fraction of all hepatic CYP proteins (2-4%) but metabolizes 25% of current meds used (opioids, anti-depressants, anti-psychotics, anti-arrhythmics)
. Activity varies in individuals: Ultra-rapid, extensive, intermediate, and poor
. Poor metabolizers make up 1-20% of pop.
. 4-5% Americans are ultra-rapid

Question 18

Thiopurine methyltransferase (TPMT)

Answer 18

. Enzyme that catalyzes addition of methyl group from adenomyosis met. As methyl donor to thiopurine analogs (drugs)

Question 19

Thiopurine drugs

Answer 19

. Azathioprine, 6-mercaptopurine, 6-thioguanine
. Treats cancer, rheumatic diseases, some skin issues, IBD, solid organ transplant rejection
. Very narrow therapuetic range (drug conc. Btw level needed to give desired effect and level that is toxic)

Question 20

Thiopurine activation in body

Answer 20

. Taken in as pro-drugs
. Converted into active form by enzymes in body
. Compounds incorporated into DNA and apoptosis is initiated

Question 21

Inactivation of thiopurine drugs

Answer 21

. Metabolized and excreted

. TPMT is primary enzyme in degradation pathway in hematopoietic cells

Question 22

Toxic effects of thiopurine drugs

Answer 22

. Inc. bone marrow toxicity/myelosuppression
. Anemia
. Bleeding tendency
. Leukopenia/infection

Question 23

Different levels of TPMT activity in individuals

Answer 23

. Normal: 90% pop., respond normally to thiopurine
. Intermediate/low: 10% pop., at risk for toxicity for thiopurine, receive 30-50% lower dose than normal
. Absent/very low: 0.3% pop., have no TMPT, extreme risk for toxic effects, should not receive thiopurines