Mechanistic Understanding of the Effect of PPIs and Acidic Carbonated Beverages on the Oral Absorption of Itraconazole Based on Absorption Modeling with Appropriate in Vitro Data

作者：Fotaki Nikoletta; Klein Sandra^*

来源：Molecular Pharmaceutics, 2013, 10(11): 4016-4023.

DOI：10.1021/mp4003249

• itraconazole
• PPI
• cola
• acidic beverage
• intragastric pH
• gastric emptying
• gastric volume
• absorption model

Proton pump inhibitors (PPIs) are potent gastric acid suppressing agents and are among the most widely sold drugs in the world. However, even though these antisecretory agents are regarded as safe, they can alter the pharmacokinetics of coadministered drugs. Due to the suppression of gastric acid secretion, they can significantly alter the intragastric pH conditions and are thus likely to affect the bioavailability of coadministered drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Among these drugs can be found itraconazole, a poorly soluble triazole-type antifungal compound. Based on observations reported in the literature, gastric pH alterations due to the coadministration of PPIs or acidic beverages can significantly decrease (PPI) or increase (e.g., Coca-Cola) the bioavailability of this compound. In the present work we estimated the fraction of itraconazole that can be absorbed (f(abs)) from Sporanox capsules or an itraconazole-HBenBCD complex formulation after oral admistration with and without coadministration of a PPI or an acidic (carbonated) beverage. For this purpose, the sensitivity of the two formulations toward the impact of various gastric variations (pH, volume, and emptying rate) as they can result from such administration conditions was studied using solubility and dissolution experiments and a physiologically based absorption model. Simulating coadministration of the two formulations with a PPI resulted in a significant (similar to 10-fold) decrease in itraconazole f(abs), indicating the pH to be essential for in vivo dissolution and subsequent absorption. The f(abs) of itraconazole after coadministration of an acidic beverage (Coca-Cola) was far lower than the f(abs) obtained for itraconazole alone and did not support the observations reported in the literature. These results clearly indicate that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, coadministered Coca-Cola is likely to alter a range of gastrointestinal parameters relevant to in vivo dissolution rather than solely affecting the intragastric pH.

• 出版日期2013-11