CYP3A4 Inhibitors

True or False: grapefruit juice is a 3A4 inhibitor that primarily affects intestinal CYP3A; therefore if the drug is administered IV, the clearance of the drug should be unaffected.

True. A single glass of regular strength grapefruit juice should not effect clearance of midazolam, cyclosporine, nifedipine. Excessive grapefruit juice WILL eventually affect hepatic clearance of 3A substrates.

True or False: With drug drug interactions, oral administration will be impacted more than I.V. administration of the object drug

True. Administration of ketoconazole with IV midazolam increased AUC by 5 fold. Administration of ketoconazole with oral midazolam increased AUC 16 fold.

True or False: CYP3A4 enzyme inhibition can be both reversible and irreversible.

True. Reversible inhibitors are competative inhibitors.

What characteristics of Midazolam make it a good probe for CYP3A4 interactions.

1.metabolism is exclusively by CYP3A4. 2. Very low renal clearance.

What is the net effect on a patient who is a CYP2C19 poor metabolizer who takes a medication that is metabolized by both CYP2C19 and CYO3A4? A. CYP3A4 metabolizes a larger fraction of the drug. B. CYP3A4 metabolizes a smaller fraction of the drug.

A. CYP3A4 metabolizes a larger fraction of the drug.

A new oral drug is a 3A4 inhibitor that results in a 4-fold increase in AUC of the object drug. This new oral drug would be classified as: A. Weak inhibitor. B. Moderate inhibitor. C. Strong inhibitor.

B. Moderate inhibitor. Moderate inhibitors cause a 2-5 fold increase in AUC. Strong inhibitors cause at least a 5 fold increase in AUC.

CYP3A inhibition is one of the most commonly encountered drug-drug interactions and has led to the market withdrawal of several drugs that are CYP3A substrates. All of the following are common features of withdrawn drugs *except*. A. Cleared predominantly by CYP3A. B. High First Pass Metabolism. C. High oral bioavailability. D. inherent risk of toxicity.

C. Is incorrect (High oral bioavailability). Drugs with potentially dangerous drug drug interactions typically have *low oral bioavailability*.

Ritonavir was initially developed as an HIV protease inhibitor, but currently used primarily as a pharmacokinetic boosting agent for HIV and hepatitis C protease inhibitors. What is the mechanism of the "boost" effect. A. Ritonovir is an inducer of 3A4. B. Ritonovir produces an active metabolite that is in inhibitor of CYP3A4. C. Ritonovir is an inhibitor of 3A4.

C. Ritonovir is an inhibitor of 3A4. Many HIV drugs are substrates of 3A4 and will have increased bioavailability, decreased clearance and longer half life when given with ritonavir.

Pharmacokinetic theory says that the __________ the fraction metabolized for the affected pathway, the __________ the increase in AUC for the parent drug when that pathway is inhibited. A. Smaller, Larger. B. Larger Smaller. C. Smaller, Smaller. D. Larger, larger.

C. the *smaller* the fraction metabolized for the affected pathway, the *smaller* the increase in AUC for the parent drug when that pathway is inhibited.

True or false: CYP3A substrates that exhibit *extensive first-pass metabolism* in the gut wall and liver will be subject to a less profound inhibitory drug-drug interaction that those substrates that are metabolized exclusively by the liver

False. Extensive first pass metabolism means that the drug has low oral bio availability. Drugs will low oral bioavailabilty have a more profound effect of drug inhibition.

True or False: The effects of a non-competitive inhibitor last as long as a the inhibitor is present.

False: In a non-reversible inhibitor, the effects of inhibition last until more enzymes can be synthesized. enzyme function is only regained when enzyme is resynthesized. with a competative (reversible) inhibitor, the effects last as long as the inhibitor is present.

'Wonder drug' is a new platelet inhibitor approved for prevention of stent thrombosis. It has been estimated that CYP2C19 accounts for 80% of wonder drug metabolism, while 20% is metabolized by CYP3A4. Which of the following scenarios would be expected to result in the highest 'wonder drug' exposure? a. Poor metabolizer of CYP2C19 receiving a concomitant inhibitor of CYP2C19 b. Extensive metabolizer of CYP2C19 receiving a concomitant inhibitor of CYP2C19 c. An ultra-rapid metabolizer of CYP2C19 receiving a concomitant inhibitor of CYP2C19 d. A poor metabolizer of CYP2C19 receiving a concomitant inhibitor of CYP3A4 e. An ultra-rapid metabolizer of CYP2C19 receiving a concomitant inhibitor of CYP3A4.

d. A poor metabolizer of CYP2C19 receiving a concomitant inhibitor of CYP3A4.