P-gp Common Substrates, Inducers, Inhibitors

Question 1

P-gp Substrates

Answer 1

• Anticoagulants (apixaban, edoxaban, dabigatran, rivaroxaban)
• Cardiovascular drugs (digoxin, diltizem, carvedilol, ranolazine, verapamil)
• Immunosuppressants (cyclosporine, sirolimus, tacrolimus)
• HCV drugs (dasabuvir, ombitasvir, paritaprevir, sofosbuvir)
• Others (atazanavir, colchicine, dolutegravir, posaconazole, raltegravir, saxagliptin)

Question 2

P-gp inducers:

Answer 2

• carbamazepine
• dexamethasone
• phenobarbital
• phenytoin
• rifampin
• St. John’s Wort
• tipranavir

Question 3

P-gp inhibitors:

Answer 3

• Anti-Infectives (clarithromycin, itraconazole, posaconazole)
• Cardiovascular drugs (amiodarone, carvedilol, conivaptan, diltiazem, dronedarone, quinidine, verapamil)
• HIV drugs (cobicistat, ritonavir)
• HCV drugs (ledipasvir, paritaprevir)
• Others (cyclosporine, flibanserin, ticagrelor)

Question 4

Amiodarone + Warfarin (can be used together for atrial fibrillation treatment: amiodarone (for rhythm), warfarin (to reduce clot risk). Dronedarone has similar drug interaction issues. Amiodarone inhibits multiple enzymes, including CYP2C9, which metabolizes the major warfarin isomer. Decreases warfarin metabolism, increases INR and bleeding risk.

Answer 4

• If using amiodarone 1st and adding warfarin. (Start warfarin at a lower dose of ≤ 5 mg)
• If using warfarin 1st and adding amiodarone. (Decrease warfarin dose 30-50%, depending on the INR).
• Taking both (Monitor INR: adjust as needed)

Question 5

Amiodarone + Digoxin (Can be given together for arrhythmia treatment: amiodarone (for rhythm), digoxin [for rate control (↓ HR), or for symptom improvement in a patient with HF].

• Amiodarone inhibits P-gp; digoxin is a P-gp substrate.
• ↓ digoxin excretion, ↑ ADRs/toxicity
• Amiodarone and digoxin both ↓ HR, ↑ risk of bradycardia, arrhythmia, fatality

Answer 5

If using amiodarone 1st and adding digoxin:
- Start oral digoxin at a low dose, such as 0.125 mg daily instead of 0.25 mg daily.
If using digoxin 1st and adding amiodarone:
- ↓ oral digoxin dose 50% (e.g. change 0.25 mg daily to 0.125 mg daily, or change 0.125 mg to 0.125 mg every other day)

Taking both amiodarone and digoxin:

1) Instruct patients to monitor for symptoms of digoxin toxicity: nausea, vomiting, vision changes; if present, contact prescriber.
2) Monitor HR: normal is 60-100 BPM (can be lower, based on patient’s history and physical state). Check for other drugs that ↓ HR: beta-blockers, clonidine, diltiazem, verapamil, dexmedetomidine (Precedex).
3) If digoxin is being used for rate control, inform prescribers to consider beta-blockers or non-DHP CCBs (preferred).

Question 6

Digoxin + Loop diuretic

Caution: HF and renal impairment often occur together. Digoxin is cleared by P-gp and excreted by the kidneys: renal impairment ↑ digoxin levels and toxicity risk. Loops decrease K, Mg, Ca, and Na. (Even without the use of a loop, electrolyte deficiencies are common with CVD). Low K, Mg, or Ca will worsen arrythmias. Digoxin toxicity risk is increased with decreased K and Mg levels, and increased Ca.

Answer 6

For patients taking both:

1) Monitor electrolytes and correct if abnormal.
2) Renal impairment: ↓ digoxin dose or frequency, or discontinue.

Question 7

Drugs that decrease HR: Diltiazem/verapamil or beta-blockers for rate control; clonidine and beta-blockers to lower BP.

-Additive effects with drugs that ↓ HR are used together, including amiodarone, digoxin, beta-blockers, clonidine and dexmedetomidine (Precedex).

Answer 7

Monitor HR: normal is 60-100 BPM (can be lower, based on patient’s history and physical state)

Question 8

Statins + Strong CYP3A4 Inhibitors

Inhibitors: ritonavir and other PIs, cobicistat, clarithromycin, erythromycin, azole antifungals, cyclosporine, grapefruit juice/fruit

Answer 8

↑ levels of CYP3A4 substrates: lovastatin, simvastatin, atorvastatin
↑ myopathy risk: if severe (with high CPK), can cause rhabdomyolysis with acute renal failure (ARF)
- Simvastatin and lovastatin are contraindicated with strong CYP3A4 inhibitors. -Recommend a statin not metabolized by CYP450 enyzmes (e.g. pitavastatin, pravastatin, rosuvastatin).

Question 9

Warfarin + Strong CYP2C9 inhibitors and inducers

• Inhibitors: azole antifungals, sulfamethoxazole/trimethoprim, amiodarone, metronidazole
• Inducers: rifampin, St. John’s Wort
• Increased levels of warfarin (↑ INR and bleeding risk) with CYP2C9 inhibitors.
• Decreased levels of warfarin (↓ INR and ↑ clotting risk) with CYP2C9 inhibitors.

Answer 9

• Monitor INR; therapeutic range is 2-3 for most conditions (2.5-3.5 for some high-risk indications, such as mechanical mitral valve).
• Some drugs (e.g. amiodarone) require prophylactic warfarin dose adjusment when started.