PHAR 751 Drug Metabolism & Interactions: Intestinal Secretion Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System

Review of Drug Metabolism and Absorption…

…in the Intestine

Mechanisms of Membrane Transport (a refresher) TypeTransport Protein? Saturation gradient? Against gradient? Energy?Examples Simple diffusion No O 2, H 2 O Ion channelYesNo Na + channel Facilitated diffusion Yes No Glucose transporter 1° Active transport Yes H + ATPase, Ca 2+ ATPas, ATP 2° Active transport Yes Na+/Ca2+ antiporter, Na+/glucose symporters

P-glycoprotein (P-gp) 170kD transmembrane glycoprotein –Member of ATP-binding cassette (ABC) transporter superfamily Encoded by MDR1 (multidrug resistance) gene Location –Apical membrane of secretory cells –High levels: Intestinal mucosa renal proximal tubules hepatocytes adrenal gland BBB Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distribution: Focus on H1-Receptor Antagonists. Clin Drug Invest 21 (8): , Posted to Medscape 8/1/01

Membrane transport: P-glycoprotein Edwards Filaria Journal (Suppl 1):S8 doi: / S1-S8

Drug absorption: effect of inhibition of P-gp Inhibition of p-gp  More drug enters = ↑ absorption P-gp action: reduced absorption of substrate Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distributioin: Focus on H1-Receptor Antagonists. Clin Drug Invest 21 (8): , Posted to Medscape 8/1/01

Substrates Accessed 2/25/07

P-gp substrates Anticancer drugs –Actinomycin D –Colchicine –Daunorubicin –Docetaxel –Doxorubicin –Etoposide –Irinotecan –Methotrexate –Mitomycin C –Mitoxantrone –Paclitaxel (Taxol) –Tamoxifen –Teniposide –Topotecan –Vinblastine –Vincristine Antihistamines –Fexofenadine –Terfenadine (DSC) Antibiotics –Cefazolin –Cefoperazone –Erythromycin –Levofloxacin –Sparfloxacin (DSC) Schwab et al. Ann Rev Pharmacol Toxicol. 2003;43:

P-gp substrates (cont.) Cardiac drugs –Digoxin –Digitoxin –Propafenone –Amiodarone –Talinolol –Quinidine HIV Protease Inhibitors –Amprenavir –Indinavir –Nelfinavir –Ritonavir –Saquinavir Morphine Derivatives –Morphine –Morphine-6- glucouronide Peptides –Gramicidin D –Valinomycin CNS drugs –Domperidone –Fluphenazine –Loperamide –Ondansetron –Perphenazine –Phenoxazine –Phenytoin Schwab et al. Ann Rev Pharmacol Toxicol. 2003;43:

P-gp substrates (cont.) Steroids –Aldosterone –Dexamethasone –Hydrocortisone Immunosuppressants –Cyclosporin A –Tacrolimus Others –Atorvastatin –Bunitrolol –Celiprolol –Irinotecan –Losartan –Lovastatin –Rifampin Schwab et al. Ann Rev Pharmacol Toxicol. 2003;43:

Inhibitors Accessed 2/25/07

P-gp inhibitors Valspodar Quinidine Verapamil Cyclosporin Spironolactone Ketoconazole Erythromycin Amiodarone Diltiazem Itraconazole Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distribution: Focus on H1-Receptor Antagonists. Clin Drug Invest 21 (8): , Posted to Medscape 8/1/01

Inducers Accessed 2/25/07

P-gp Inducers Rifampin Phenobarbital Clotrimazole Reserpine Isosafrole Midazolam Glucocorticoids Nifedipine Quercetin Kaempferol Galanin St. John’s Wort Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distributioin: Focus on H1-Receptor Antagonists. Clin Drug Invest 21 (8): , Posted to Medscape 8/1/01

Greiner, et al. The role of intestinal p-glycoprotein in the interaction of digoxin and rifampin. J Clin Investig. 104:147(2) Substrate: Digoxin po (a) Digoxin IV (b) Inducer: Rifampin  Interaction in the intestine  Induction of p-gp P-gp induction

P-gp induction: duodenal biopsies Greiner, et al. The role of intestinal p-glycoprotein in the interaction of digoxin and rifampin. J Clin Investig. 104:147(2)

PK: Digoxin w/ and w/o Rifampin Greiner, et al. The role of intestinal p-glycoprotein in the interaction of digoxin and rifampin. J Clin Investig. 104:147(2)

Talinolol w/ and w/o Rifampin Westphal, et al. Induction of p-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction. Clin Pharmacol Ther 2000;68: Study design: IV & po

PK: Talinolol w/ and w/o Rifampin Westphal, et al. Induction of p-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction. Clin Pharmacol Ther 2000;68: IVOral

PK: Talinolol w/ and w/o Rifampin Westphal, et al. Induction of p-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction. Clin Pharmacol Ther 2000;68:

Clearance: p-gp + systemic  Multiple routes of clearance

Another study… Loperamide + Quinidine PK Sadeque, et al. Increased drug delivery to the brain by p-glycoprotein inhibition. Clin Pharmacol Ther 2000;68: A: [Loperamide] B: [Metabolite]

Loperamide + Quinidine PD Sadeque, et al. Increased drug delivery to the brain by p-glycoprotein inhibition. Clin Pharmacol Ther 2000;68:231-7.

PK + PD Loperamide w/ and w/o Quinidine Sadeque, et al. Increased drug delivery to the brain by p-glycoprotein inhibition. Clin Pharmacol Ther 2000;68:231-7.