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