Pharm Exam 1

Question 1

1 potent inhibitor of OAT?

* Why is it given w/cidefovir? (explain)

Answer 1

Probenecid
- Given w/cidefovir to protect from otherwise severe renal toxicity by blocking uptake into the proximal tubules (from the blood)

Question 2

3 Drugs transported by OAT?

Answer 2

Ci-Me-N

• Cidefovir
• Methotrexate
• NSAIDs

Question 3

1 drug class transported by OATP?

Answer 3

Statins

Question 4

1 potent inhibitor of OATP?

* If given w/statins, where would it inhibit the uptake of statins and what would this cause?

Answer 4

Cyclosporin

- Inhibits statin uptake from blood to liver, increasing toxicity risk and decrease statin efficacy

Question 5

4 Drugs transported by OCT?

Answer 5

Ci-Ci, pro met

• Cisplatin
• Cimetidine
• Procainamide
• Metformin

Question 6

2 Drugs transported by P-gp/MDR-1?

Answer 6

• Digoxin

- Loperamide

Question 7

1 potent inhibitor of P-gp/MDR-1?

Answer 7

Cyclosporin

Question 8

St. John’s Wort and rifampin induce which transporter protein type?

Answer 8

P-gp/MDR-1?

Question 9

1 drug class transported by BCRP?

Answer 9

Statins

Question 10

3 endogenous substrates of MRP?

Answer 10

• Glutathione
• Glucuronide
• Sulfate-conjugates

Question 11

What drugs induce expression of CYP450 enzymes?

Answer 11

Phen-Phen rifles St. John’s glowing pink cars.

• Phenytoin
• Phenobarbitol
• Rifampin
• St. John’s wort
• Glucocorticoids
• Pioglitazone
• Carbamazepine

Question 12

What drugs inhibit expression of CYP450 enzymes?

Answer 12

Eric’s red grape kept its clear fluid

• Erythromycin
• Ritonavir
• Grapefruit juice (enterocytes, NOT liver)
• Ketoconazole
• Itraconazole
• Clarithromycin
• Fluconazole

Question 13

E.g. of drug class that may compete for protein binding and increase the unbound fraction of other drugs?

Answer 13

Sulfanomides

Question 14

2 drugs eliminated by zero-order kinetics?

Answer 14

• Phenytoin

- Alcohol

Question 15

3 types of rxns involved in phase I rxns?

Answer 15

• Oxidation (CYP450)
• Reduction
• Hydrolysis

Question 16

3 most common CYP450 enzyme subfamilies?

Answer 16

• 3A
• 2C
• 2D

Question 17

What classes of biochemical binding-site interactions are irreversible inhibitors of CYP3A4? (1). Reversible? (2)

Answer 17

• REVERSIBLE: Competitive or allosteric

- IRREVERSIBLE: Suicide inhibitor (covalent binding)

Question 18

Is gray baby syndrome related to phase 1 or 2 enzymes? (Excess or deficiency?)
- What drug leads to it?

Answer 18

• Phase 2 deficiency
• Chloramphenicol
  (results in circulatory collapse and cyanosis)

Question 19

Chemicals in cigarette smoke, charbroiled food and cruciferous vegetables all induce CYP___.

Answer 19

1A2

Question 20

Chronic alcohol induces expression of CYP___

Answer 20

2E1

Question 21

Substrate specificity for OAT?

Answer 21

Broad range of low MW substrates

Question 22

Substrate specificity for OATP?

Answer 22

Broad range of substrates; Amphipathic Anions, MW > 350 Da

Question 23

Most drug interactions mediated by OCT/MATE are caused by what drug?
- How? (what organ)

Answer 23

Cimetidine

- Prevents renal elimination of other OCT-dependent drugs

Question 24

What 2 channels does cyclosporin inhibit?

Answer 24

OATP and P-gp/MDR-1

Question 25

What 2 channels transport statins?

Answer 25

- OATP (influx) | - BCRP (efflux)

Question 26

What drug is given w/cisplatin to avoid nephrotoxicity?

Answer 26

Cimetidine.

Question 27

Substrate specificity for P-gp/MDR-1?

Answer 27

- Broad substrate specificity, typically bulky hydrophobic structures with neutral/positive charge

Question 28

Would tumor cells upregulate or downregulate p-gp/MDR-1? Why?

Answer 28

Tumor cells often upregulate expression of P-gp/MDR1 to promote efflux of anti-cancer drugs

Question 29

Of the transporters mentioned, which one is not present at the apical gut lumen?

Answer 29

OAT

Question 30

Name the 3 most common CYP polymorphic genes.

Answer 30

CYP2D6, 2C9 and 2C19

Question 31

Which of the CYP proteins is linked to warfarin inactivation of the active metabolite, S-warfarin?

Answer 31

CYP2C9

Question 32

How does VCORC1 relate to warfarin? What does VCORC1 do What would happen with a mutation in VCORC1?

Answer 32

- Warfarin nlly inhibits VCORC1 - VCORC1 leads to formation of active clotting factor - VCORC1 mutation = warfarin resistance = low anticoagulation (need higher dose)

Question 33

What are the 3 non-pharmacological means of antagonizing drug effects?

Answer 33

1. Chemical antagonism (e.g. chelation) 2. Physiologic antagonism (use of opposing pw's) 3. Biologic antagonism (1 drug effects metab/PK of another)

Question 34

How is 95% of acetaminophen metabolized? What about the other 5%? Why is high dose dangerous? * Treatment with what drug will elevate glutathione levels and shunt back to normal pw?

Answer 34

- 95% is conjugated and eliminated - 5% converted to NAPQI, which can be conjugated - High dose shunts pw to NAPQI -> hepatotoxicity - N-acetyl cysteine

Question 35

Explain (in small amount of detail) the 5 parts of pre-clinical trials. 1) What 2 doses must be determined?

Answer 35

1. Safety pharmacology (no effect dose + LD50) 2. Toxicology 3. PK testing (ADME) 4. Drug interactions (CYP450, xporters) 5. Chemical/pharmacological devo (stable? reproducible?)

Question 36

When does the FDA perform a review in the making of a new drug?

Answer 36

- Reviews investigational new drug application (INDA) - Meets b/w phase II and III of clinical trials (to be sure it's safe for larger pop.) - Reviews new drug application (NDA)

Question 37

What are the 3 things an IND application must have?

Answer 37

1. Animal pharm and toxicology data 2. Manufacturing info 3. Clinical protocols/investigator info - Shows drug is reasonably safe and allows drug to be shipped across state lines

Question 38

1. Purposes of phase I trial? | 2. Trial design?

Answer 38

1. Is it safe/tolerable; PK | 2. Open label w/escalating dose

Question 39

1. Purposes of phase II trial? | 2. Trial design?

Answer 39

1. Does it work in actual pts? Dosing; Efficacy; safety | 2. Single/double-blind

Question 40

Purposes of phase III trial? | Trial design?

Answer 40

1. Does it work in large pt population? Efficacy + safety | 2. Double-blind

Question 41

What 4 things must be labeled on drug packaging?

Answer 41

1. Dosage 2. Adverse reactions 3. Contraindications 4. Special warnings/precautions

Question 42

Define the 3 classes of drug recall.

Answer 42

Class I: Reasonable probability that use of drug will cause serious adverse health consequences or death (e.g. microbial contamination) Class II: Use of drug will cause temporary adverse health consequences, although probability of serious health consequences is remote Class III: Use of drug is unlikely to cause adverse health consequences (e.g. quantity packaging error)

Question 43

What can happen when loperamide is given concurrently w/cyclosporin?

Answer 43

P-gp/MDR-1 receptors can be inhibited by cyclosporin, allowing loperamide to cross BBB can cause respiratory depression.

Question 44

Which protein transporter class has specificity that overlaps with CYP3A4?

Answer 44

P-gp/MDR-1

Question 45

In what phase of clinical trials of "proof of concept" established?

Answer 45

Phase II