Periodic Reporting for period 1 - pH4HIF (Effect of pH on colloidal structures in human intestinal fluids and intestinal absorption of anticancer drugs)
Période du rapport: 2023-09-01 au 2025-08-31
Improving oral drug delivery is crucial for ensuring safe and effective treatment. A major challenge in oral drug delivery is the significant variability in intestinal drug absorption. This variability is largely influenced by the complex and dynamic composition of human intestinal fluids (HIF), which differs among individuals and is affected by whether a person is in a fed or fasted state.
HIF contains various components such as bile salts, cholesterol, proteins, phospholipids, and lipids, and its pH can vary widely. These factors play a key role in how well a drug dissolves and is absorbed in the intestine. Understanding the mechanisms of drug absorption is particularly important, as changes in pH and food intake can lead to drug under- or overdose.
One promising approach to better understand intestinal drug absorption is to investigate the pH effect. pH can influence drug absorption in two main ways. The first is a direct effect, where pH changes the ionization of the drug, which is a well-known mechanism. The second is an indirect effect, where pH alters the colloidal structures in HIF, also impacting drug absorption. Although the indirect pH effect is much less understood, it may play a significant role in affecting drug solubility and absorption.
The overall objective of this project was to investigate the pH effect on the colloidal structures of HIF in the fed state and its impact on drug solubility.
HIF contains various components such as bile salts, cholesterol, proteins, phospholipids, and lipids, and its pH can vary widely. These factors play a key role in how well a drug dissolves and is absorbed in the intestine. Understanding the mechanisms of drug absorption is particularly important, as changes in pH and food intake can lead to drug under- or overdose.
One promising approach to better understand intestinal drug absorption is to investigate the pH effect. pH can influence drug absorption in two main ways. The first is a direct effect, where pH changes the ionization of the drug, which is a well-known mechanism. The second is an indirect effect, where pH alters the colloidal structures in HIF, also impacting drug absorption. Although the indirect pH effect is much less understood, it may play a significant role in affecting drug solubility and absorption.
The overall objective of this project was to investigate the pH effect on the colloidal structures of HIF in the fed state and its impact on drug solubility.
HIF samples were collected from the duodenum (the first part of the small intestine) after volunteers consumed half of a standard FDA breakfast (toast, eggs, bacon, and milk). The collected HIF samples were analysed for their content of lipids, proteins, bile salts, and phospholipids; additionally, pH was measured.
Samples collected after a solid meal (half of the FDA breakfast) were compared with those collected after a liquid meal. The results showed that the composition of HIF depends on the type of food, with the greatest differences observed in the concentration of lipids, cholesterol, and proteins, as well as in the extent of lipid digestion. This suggests that both food type and pH can influence how well drugs dissolve and are absorbed in the body.
To study the indirect pH effect, the HIF samples were pooled based on the time after eating. The pH of each pool was adjusted to values between 4 and 7, covering the reported pH range in the small intestine. These samples were then used to assess the solubility of selected drugs across different pH levels.
Only poorly soluble, neutral drugs were tested as these are not directly affected by pH changes. Still, the results showed a strong pH effect on drug solubility, indicating that pH-induced changes in the colloidal structure of HIF can affect drug solubility even for neutral drugs. Interestingly, the pH at which drugs dissolved the most varied depending on whether samples were collected after a solid or a liquid meal.
Further analysis revealed that larger colloidal structures, which facilitate drug dissolution, formed at lower pH levels. These structures also differed between HIF samples collected after solid and liquid meals, indicating that the type of food can significantly influence drug solubility and the behaviour of intestinal fluids.
For comparison, similar tests were conducted using commercially available simulated intestinal fluids (SIF), commonly used in drug development. Adding sodium oleate, which mimics free fatty acids, to SIF showed a strong pH dependence: drug solubility increased by up to 100 times at acidic pH compared to SIF without oleate. This effect was more pronounced for the more hydrophobic drugs, likely because they dissolve better in the oily droplets that form at low pH.
However, the solubility patterns in real HIF remained quite different from those in SIF, even with modified SIF. This suggests that current laboratory models may not fully capture the complex behaviour of real intestinal fluids, particularly in terms of pH-related effects.
Samples collected after a solid meal (half of the FDA breakfast) were compared with those collected after a liquid meal. The results showed that the composition of HIF depends on the type of food, with the greatest differences observed in the concentration of lipids, cholesterol, and proteins, as well as in the extent of lipid digestion. This suggests that both food type and pH can influence how well drugs dissolve and are absorbed in the body.
To study the indirect pH effect, the HIF samples were pooled based on the time after eating. The pH of each pool was adjusted to values between 4 and 7, covering the reported pH range in the small intestine. These samples were then used to assess the solubility of selected drugs across different pH levels.
Only poorly soluble, neutral drugs were tested as these are not directly affected by pH changes. Still, the results showed a strong pH effect on drug solubility, indicating that pH-induced changes in the colloidal structure of HIF can affect drug solubility even for neutral drugs. Interestingly, the pH at which drugs dissolved the most varied depending on whether samples were collected after a solid or a liquid meal.
Further analysis revealed that larger colloidal structures, which facilitate drug dissolution, formed at lower pH levels. These structures also differed between HIF samples collected after solid and liquid meals, indicating that the type of food can significantly influence drug solubility and the behaviour of intestinal fluids.
For comparison, similar tests were conducted using commercially available simulated intestinal fluids (SIF), commonly used in drug development. Adding sodium oleate, which mimics free fatty acids, to SIF showed a strong pH dependence: drug solubility increased by up to 100 times at acidic pH compared to SIF without oleate. This effect was more pronounced for the more hydrophobic drugs, likely because they dissolve better in the oily droplets that form at low pH.
However, the solubility patterns in real HIF remained quite different from those in SIF, even with modified SIF. This suggests that current laboratory models may not fully capture the complex behaviour of real intestinal fluids, particularly in terms of pH-related effects.
The project provided new insights into the influence of pH on drug solubility in the small intestine. While it is well known that pH can directly influence drug ionization and thus drug properties, this study revealed that pH also has a significant indirect effect by altering the colloidal structures in HIF. These structural changes, in turn, impact how well drugs dissolve and are absorbed.
A major breakthrough was the discovery that the type of food (solid vs. liquid) and pH levels together influence the composition and solubilizing capacity of HIF in ways that were previously uncharacterized. The study revealed that larger colloidal structures form at acidic pH levels and that these structures change depending on the type of meal consumed. This finding highlights a previously overlooked mechanism that affects drug absorption variability under different nutritional states.
Furthermore, the comparison with SIF revealed that even modified SIF systems fail to fully replicate the complex pH-dependent behavior of real HIF. This questions the current dependence on SIF in drug development and highlights the need for more physiologically relevant media.
A major breakthrough was the discovery that the type of food (solid vs. liquid) and pH levels together influence the composition and solubilizing capacity of HIF in ways that were previously uncharacterized. The study revealed that larger colloidal structures form at acidic pH levels and that these structures change depending on the type of meal consumed. This finding highlights a previously overlooked mechanism that affects drug absorption variability under different nutritional states.
Furthermore, the comparison with SIF revealed that even modified SIF systems fail to fully replicate the complex pH-dependent behavior of real HIF. This questions the current dependence on SIF in drug development and highlights the need for more physiologically relevant media.