Pharm Exam 1 Flashcards
1 potent inhibitor of OAT?
* Why is it given w/cidefovir? (explain)
Probenecid
- Given w/cidefovir to protect from otherwise severe renal toxicity by blocking uptake into the proximal tubules (from the blood)
3 Drugs transported by OAT?
Ci-Me-N
- Cidefovir
- Methotrexate
- NSAIDs
1 drug class transported by OATP?
Statins
1 potent inhibitor of OATP?
* If given w/statins, where would it inhibit the uptake of statins and what would this cause?
Cyclosporin
- Inhibits statin uptake from blood to liver, increasing toxicity risk and decrease statin efficacy
4 Drugs transported by OCT?
Ci-Ci, pro met
- Cisplatin
- Cimetidine
- Procainamide
- Metformin
2 Drugs transported by P-gp/MDR-1?
- Digoxin
- Loperamide
1 potent inhibitor of P-gp/MDR-1?
Cyclosporin
St. John’s Wort and rifampin induce which transporter protein type?
P-gp/MDR-1?
1 drug class transported by BCRP?
Statins
3 endogenous substrates of MRP?
- Glutathione
- Glucuronide
- Sulfate-conjugates
What drugs induce expression of CYP450 enzymes?
Phen-Phen rifles St. John’s glowing pink cars.
- Phenytoin
- Phenobarbitol
- Rifampin
- St. John’s wort
- Glucocorticoids
- Pioglitazone
- Carbamazepine
What drugs inhibit expression of CYP450 enzymes?
Eric’s red grape kept its clear fluid
- Erythromycin
- Ritonavir
- Grapefruit juice (enterocytes, NOT liver)
- Ketoconazole
- Itraconazole
- Clarithromycin
- Fluconazole
E.g. of drug class that may compete for protein binding and increase the unbound fraction of other drugs?
Sulfanomides
2 drugs eliminated by zero-order kinetics?
- Phenytoin
- Alcohol
3 types of rxns involved in phase I rxns?
- Oxidation (CYP450)
- Reduction
- Hydrolysis
3 most common CYP450 enzyme subfamilies?
- 3A
- 2C
- 2D
What classes of biochemical binding-site interactions are irreversible inhibitors of CYP3A4? (1). Reversible? (2)
- REVERSIBLE: Competitive or allosteric
- IRREVERSIBLE: Suicide inhibitor (covalent binding)
Is gray baby syndrome related to phase 1 or 2 enzymes? (Excess or deficiency?)
- What drug leads to it?
- Phase 2 deficiency
- Chloramphenicol
(results in circulatory collapse and cyanosis)
Chemicals in cigarette smoke, charbroiled food and cruciferous vegetables all induce CYP___.
1A2
Chronic alcohol induces expression of CYP___
2E1
Substrate specificity for OAT?
Broad range of low MW substrates
Substrate specificity for OATP?
Broad range of substrates; Amphipathic Anions, MW > 350 Da
Most drug interactions mediated by OCT/MATE are caused by what drug?
- How? (what organ)
Cimetidine
- Prevents renal elimination of other OCT-dependent drugs
What 2 channels does cyclosporin inhibit?
OATP and P-gp/MDR-1
What 2 channels transport statins?
- OATP (influx)
- BCRP (efflux)
What drug is given w/cisplatin to avoid nephrotoxicity?
Cimetidine.
Substrate specificity for P-gp/MDR-1?
- Broad substrate specificity, typically bulky hydrophobic structures with neutral/positive charge
Would tumor cells upregulate or downregulate p-gp/MDR-1? Why?
Tumor cells often upregulate expression of P-gp/MDR1 to promote efflux of anti-cancer drugs
Of the transporters mentioned, which one is not present at the apical gut lumen?
OAT
Name the 3 most common CYP polymorphic genes.
CYP2D6, 2C9 and 2C19
Which of the CYP proteins is linked to warfarin inactivation of the active metabolite, S-warfarin?
CYP2C9
How does VCORC1 relate to warfarin?
What does VCORC1 do
What would happen with a mutation in VCORC1?
- Warfarin nlly inhibits VCORC1
- VCORC1 leads to formation of active clotting factor
- VCORC1 mutation = warfarin resistance = low anticoagulation (need higher dose)
What are the 3 non-pharmacological means of antagonizing drug effects?
- Chemical antagonism (e.g. chelation)
- Physiologic antagonism (use of opposing pw’s)
- Biologic antagonism (1 drug effects metab/PK of another)
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?
- 95% is conjugated and eliminated
- 5% converted to NAPQI, which can be conjugated
- High dose shunts pw to NAPQI -> hepatotoxicity
- N-acetyl cysteine
Explain (in small amount of detail) the 5 parts of pre-clinical trials.
1) What 2 doses must be determined?
- Safety pharmacology (no effect dose + LD50)
- Toxicology
- PK testing (ADME)
- Drug interactions (CYP450, xporters)
- Chemical/pharmacological devo (stable? reproducible?)
When does the FDA perform a review in the making of a new drug?
- 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)
What are the 3 things an IND application must have?
- Animal pharm and toxicology data
- Manufacturing info
- Clinical protocols/investigator info
- Shows drug is reasonably safe and allows drug to be shipped across state lines
- Purposes of phase I trial?
2. Trial design?
- Is it safe/tolerable; PK
2. Open label w/escalating dose
- Purposes of phase II trial?
2. Trial design?
- Does it work in actual pts? Dosing; Efficacy; safety
2. Single/double-blind
Purposes of phase III trial?
Trial design?
- Does it work in large pt population? Efficacy + safety
2. Double-blind
What 4 things must be labeled on drug packaging?
- Dosage
- Adverse reactions
- Contraindications
- Special warnings/precautions
Define the 3 classes of drug recall.
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)
What can happen when loperamide is given concurrently w/cyclosporin?
P-gp/MDR-1 receptors can be inhibited by cyclosporin, allowing loperamide to cross BBB can cause respiratory depression.
Which protein transporter class has specificity that overlaps with CYP3A4?
P-gp/MDR-1
In what phase of clinical trials of “proof of concept” established?
Phase II
