Lecture 16 - Victim and Perpetrator & Inducers/inhibitors

Victim drug - Ciprofloxacin (Antibiotic)

Perpetrator - antacid

Victim Drug - Digoxin (treat congestive heart failure)

Perpetrator - erythromycin (antibiotic)

Victim Drug - Tetracycline & quinolone (antibiotics)

Perpetrators - Divalent & trivalent ions

(Ca²⁺, Al³⁺, Mg²⁺, Fe³⁺, Zn²⁺, antacids, milk)

Victim drug - Warfarin (anionic drugs)

Perpetrator - Cholestyramine (Cationic resins)

Perpetrators for: Increase gastric emptying and GI motility - ‘Prokinetic’ drugs

Metoclopramide, Cisapride (canada), Domperiodone (outside US)

Perpetrator for: Decrease gastric emptying and GI motility

Anticholinergic drugs such as diphenhydramine

Victim drug - Warfarin (anticoagulant; 99% binding)

Perpetrator - Phenylbutazone

Outcome - Increase clotting time, risk of hemorrhage

Victim drug - Tolbutamide (Diabetic drug; 99% binding)

Perpetrator - Sulfonamides

Outcome - Enhanced Hypoglycemia

Victim Drugs - Corticosteroids, oral contraceptives, warfarin, phenytoin

Perpetrator Drugs - Phenobarbital, Rifampin

Outcome - Decrease plasma levels and efficacy

P450 Inducers - 1A2

• Benzo(a)pyrene

• Omeprazole

• Phenobarbital

• Rifampin

P450 Inducers - 2C19

• Carbamazepine

• Phenobarbital

• Rifampin

• Phenytoin

P450 Inducers - 2C9

• Secobarbital

• Phenobarbital

• Rifampin

• Phenytoin

P450 Inducers - 2E1

• Chronic Ethanol

• Isoniazid

P450 inducers - 3A4

• Carbamazepine

• Dexamethasone

• Efavirenz

• Pioglitazone

• St. John’s wort

• Phenobarbital

• Rifampin

• Phenytoin

Victim Drugs - Tyramine-rich foods

Perpetrator Drug - MAO inhibitor

Outcome - Enhanced absorption of Tyramine

Victim Drug - Warfarin

Perpetrator Drug - Metronidazole

Outcome - Increase anticoagulant activity

Victim Drug - Alcohol

Perpetrator Drug - Disulfiram, metronidazole

Outcome - Increase Acetaldehyde levels (flushing reaction)

P450 Inhibitors - 1A2

• Cimetidine

• Macrolides - clarithromycin, erythromycin

P450 Inhibitors - 2C19

• Cimetidine

• Ritonavir

• Antidepressants (SSRIs) - fluoxetine, fluvoxamine, setraline

P450 - 2C9

• Cimetidine

• Amiodarone

• Ritonavir

• Azole antigfungals - fluconazole, itraconazole, ketoconazole

• Antidepressants - Fluoxetine, Fluvoxamine, sertraline

P450 - 2D6

• Cimetidine

• Amiodarone

• Antidepressants - Clomipramine, Desipramine, Fluoxetine, Fluvoxamine, Sertraline, Paroxetine, Amitriptyline, Buproprion

P450 Inhibitors - 2E1

Disulfiram

P450 Inhibitor - 3A4

• Cimetidine

• Amiodarone

• Ritonavir

• Azole antifungals - fluconazole, itraconazole, ketoconazole

• Antidepressants - fluoxetine, fluvoxamine

• Macrolides - erythromycin

• Grapefruit juice

Victim Drug - Metformin (Diabetes)

Perpetrator - Cimetidine (ulcer medication)

Victim Drug - Oral contraceptive

Perpetrator - Penicillin

P-glycoprotein Substrates

• Cyclosporine

• Digoxin

• Doxorubicin

• Paclitaxel

P-glycoprotein Inhibitors

• Amiloride

• Amiodarone

• Atorvastatin

• Verapamil

P-glycoprotein Inducers

• Grapefruit juice (?)

• Paclitaxel

• Rifampin (PXR)

• St. John’s wort (PXR)

Victim Drug - Ace inhibitors, some Diuretics (Potassium-Sparing drugs)

Perpetrator - Potassium Supplements

Outcome - Lead to Hyperkalemia

Victim drug - Warfarin

Perpetrator - Vitamin K

Victim Drug - Antihypertensive drugs

Perpetrator - Licorice candy

Mechanisms - Grapefruit

• Metabolism: Decrease CYP3A4/5 in intestines

• Transporter: Inhibit OATP142 (intestine) and OATP1B1, 1B3 and 2B1 (liver)

Drug Interactions - Grapefruit juice

• Calcium channel blockers (Felodipine)

• Psychiatric medications (Sertraline)

• Cholesterol Inhibitors (Statins)

• Erectile Dysfunction (Sildenafil)