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How Proton Pump Inhibitors (i.e., omeprazole, lansoprazole) Decrease the Absorption of Itraconazole (Sporanox)

Summary:

  • The triazole antifungal medication, itraconazole (Sporanox) is commonly used in the treatment of both superficial and systemic fungal infections.  Successful treatment of systemic or invasive fungal infections is dependent on consistent plasma itraconazole levels.
  • Unfortunately, the encapsulated formulation of itraconazole has been associated with wide variability in plasma concentrations due to variability in absorption from the gastrointestinal (GI) tract. 
  • Encapsulated itraconazole requires an acidic pH in the stomach for the proper dissolution and absorption in the duodenum (small intestine).
  • Proton pump inhibitor medications can increase the gastric pH and thereby decrease the dissolution of the capsule and the amount of itraconazole available for absorption from the GI tract for systemic delivery.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: October 2015

Explanation

  • The triazole antifungal medication, itraconazole (Sporanox) is used for the treatment of both superficial and systemic fungal infections.  Successful treatment of systemic or invasive fungal infections is dependent on consistent plasma itraconazole levels.1-3  Unfortunately, the encapsulated formulation of itraconazole has been associated with wide variability in plasma concentrations due to variability in absorption in the gastrointestinal (GI) tract.  This variability can be exaggerated by coadministration with antacids or proton pump inhibitors (PPI; e.g.., omeprazole, lansoprazole, pantoprazole)4  Fortunately, this is not the case with the oral solution or intravenous (IV) formulations of itraconazole.

    Why is there such variability in  absorption with the encapsulated form of itraconazole?

    One factor known to affect plasma concentrations is the ability of the capsule to dissolve in the stomach so that the itraconazole can be released for absorption in the GI tract.  Proper dissolution of the encapsulated itraconazole requires an acidic pH of 1-4 in the stomach.5  Itraconazole is a highly lipophilic (lipid loving) weak base with a pKa = 3.7 (the pH where it ionizes or is charged) that is insoluble in water.6  It is insoluble in water because the pH of water is >4, thereby causing the itraconazole to be in its nonionized state (without a charge).  (Note: Particles in their nonionized (or uncharged) state are more lipophilic and less soluble in water.)  Since orally delivered itraconazole is likely to be administered with water and come in contact with the moisture in our oropharynx and esophagus, encapsulating itraconazole protects it from being in an insoluble state until gets into the stomach.  Once the encapsulated itraconazole gets into the stomach, the acidic environment will cause dissolution/disintegration of the capsule and improved solubility of the itraconazole since it will be ionized or charged and able to interact with fluids in preparation for delivery into the duodenum (small intestine).  This process will allow for more itraconazole to be delivered into the duodenum where the pH becomes more alkaline/basic (i.e. pH > 3.7) because of the bicarbonate secretions from both the bile and pancreatic fluids.  The alkaline environment of the duodenum then causes itraconazole to be put back into its nonionized state.  This change promotes systemic absorption by crossing the cell membranes of the enterocytes and via P-glycoprotein transporters in the lining of the lumen of the GI tract.  Therefore, anything that increases the pH above 3.7 (making the gastric fluid more alkaline or basic) will decrease the dissolution/disintegration of the encapsulated itraconazole and thus decrease the amount of itraconazole available for absorption in the duodenum.4,5  Unfortunately, PPIs can easily increase the gastric pH > 4 for a significant portion of each day by irreversibly inhibiting the proton pump located on the luminal side of the parietal cells (or oxyntic cells).4,5,7-9

    Is the reduction in absorption of itraconazole by PPIs clinically significant?

    Yes.  In fact, one pharmacokinetic study evaluating the coadministration of omeprazole and oral itraconazole reported a 64% reduction in the mean area under the curve (AUC) and a 66% reduction in maximal concentrations.4  Data such as this show why these reductions in absorption can increase the risk for variations in plasma concentration and possibly decrease the therapeutic efficacy of oral itraconazole.  Interestingly, administering Coca-Cola (an acidic beverage) with oral itraconazole can increase the absorption two fold in most patients.10  While this may be helpful in some patients, it may not be reliable.  As such, the use of oral solution or IV itraconazole or another recommended antifungal without dissolution concerns in the presence of a PPI would be preferred.

    References:

    1. Poirier JM, Cheymol G.  Optimization of itraconazole therapy using target drug concentrations.  Clin Pharmacokinet  1998;35:461-73.       
    2. Glasmacher A, Molitor E, Hahn C et al.  Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukemia.  Leukemia  1998;12:1338-43.
    3. Boogaerts MA, Verhoef GE, Zachee P et al.  Antifungal prophylaxis with itraconazole in prolonged neutropenia: correlation with plasma levels.  Mycoses  1989;32:103-8.
    4. Jaruratanasirikul S, Sriwiriyanjan S.  Effect of omeprazole on the pharmacokinetics of itraconazole.  Eur J Clin Pharmacol  1998;54:159-61.
    5. Lange D, Pavao JH, Wu J et al.  Effect of cola beverage on the bioavailability of itraconazole in the presence of H2 blockers.  J Clin Pharmacol  1997;37:535-40.
    6. Itraconazole (Sporanox) product package insert.  Janssen Pharmaceutica N.V.  Titusville, NJ.  April 2008.
    7. Blum RA, Shi H, Karol MD et al.  The comparative effects of lansoprazole, omeprazole, and ranitidine in suppressing gastric acid secretion.  Clin Ther  1997;19:1013-23.
    8. Pisegna JR.  Treating patients with acute gastrointestinal bleeding or rebleeding.  Pharmacotherapy  2003;23:81S-86S.
    9. Welage LS.  Pharmacologic properties of proton pump inhibitors.  Pharmacotherapy  2003;23:74S-80S.
    10. Jaruratanasirikul S, Kleepkaew A.  influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole.  Eur J Clin Pharmacol  1997;52:235-7.

MESH Terms & Keywords

  • Proton Pump Inhibitor, PPI, Omeprazole, Prilosec, Lansoprazole, Prevacid, Dexlansoprazole, Dexilant, Pantoprazole, Protonix, Rabeprazole, Aciphex, Itraconazole, Sporanox