PHAR 751 Drug Metabolism

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PHAR 751 Drug Metabolism Interactions
Intestinal Secretion

• Sarah Brown, Pharm.D.
• Pharmacy Practice Resident
• Asante Health System

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Review of Drug Metabolism and Absorption
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in the Intestine
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Mechanisms of Membrane Transport (a refresher)
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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)587-596,
2001. Posted to Medscape 8/1/01
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Membrane transport P-glycoprotein
Edwards Filaria Journal 2003 2(Suppl 1)S8  
doi10.1186/1475-2883-2-S1-S8
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Drug absorption effect of inhibition of P-gp
P-gp action reduced absorption of substrate
Inhibition of p-gp ? More drug enters ?
absorption
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)587-596, 2001. Posted to Medscape 8/1/01
8
Substrates
http//en.wikipedia.org/wiki/Morphine Accessed
2/25/07
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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.
200343285-307
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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.
200343285-307
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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.
200343285-307
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Inhibitors
http//images.google.com Accessed 2/25/07
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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)587-596,
2001. Posted to Medscape 8/1/01
14
Inducers
http//images.google.com Accessed 2/25/07
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P-gp Inducers

• Rifampin
• Phenobarbital
• Clotrimazole
• Reserpine
• Isosafrole
• Midazolam
• Glucocorticoids

• Nifedipine
• Quercetin
• Kaempferol
• Galanin
• St. Johns 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)587-596, 2001. Posted to Medscape 8/1/01
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P-gp induction
Substrate Digoxin po (a) Digoxin IV
(b) Inducer Rifampin ? Interaction in the
intestine ? Induction of p-gp
Greiner, et al. The role of intestinal
p-glycoprotein in the interaction of digoxin and
rifampin. J Clin Investig. 104147(2) 147-153.
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P-gp induction duodenal biopsies
Greiner, et al. The role of intestinal
p-glycoprotein in the interaction of digoxin and
rifampin. J Clin Investig. 104147(2) 147-153.
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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. 104147(2) 147-153.
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Talinolol w/ and w/o Rifampin
Study design IV po
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
200068345-55.
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PK Talinolol w/ and w/o Rifampin
IV Oral
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
200068345-55.
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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
200068345-55.
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Clearance p-gp systemic
? Multiple routes of clearance
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
200068345-55.
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Another study Loperamide Quinidine PK
A Loperamide B Metabolite
Sadeque, et al. Increased drug delivery to the
brain by p-glycoprotein inhibition. Clin
Pharmacol Ther 200068231-7.
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Loperamide Quinidine PD
Sadeque, et al. Increased drug delivery to the
brain by p-glycoprotein inhibition. Clin
Pharmacol Ther 200068231-7.
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PK PDLoperamide w/ and w/o Quinidine
Sadeque, et al. Increased drug delivery to the
brain by p-glycoprotein inhibition. Clin
Pharmacol Ther 200068231-7.