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The Effect of pH Stability and Aqueous Solubility on the Oral Bioavailability of A Novel Antileishmanial Agent
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DOI：10.1016/j.ejps.2026.107585.png)
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Abstract
En 中文
OJT007 is a novel drug class with potent antiproliferative effects against Leishmania Major. The drug is amphoteric with a key basic amine pKa of 5.8 and acid liable. Pre-systemic metabolism in gastric acidic compartment is suspected as a major factor for its low oral bioavailability. To validate this biopharmaceutical assumption, we evaluated in vitro stability and solubility profiles of OJT007 in various buffers (pH 1.2-7). We further conducted a pharmacokinetic drug-drug interaction study where OJT007 was orally administered alone or following pre-treatment of rabeprazole, a prescription proton pump inhibitor that reduces stomach acid using rat as an animal model. The in vitro degradation of OJT007 was rapid at pH 1.2-3 with less than 50% drug remaining within 30 min. Solubility of OJT007 was also pH-dependent with a solubility of 31.3 µg/mL at pH 1.2 and practically insoluble at pH above 6. Interestingly in the in vivo studies, there were approximately 40% reduction in the mean maximum plasma drug concentration (Cmax) and the mean area under the plasma concentration versus time curve (AUC0-∞) in the rat group pre-treated with rabeprazole as compared to OJT007 alone. As opposed to our initially hypothesized, OJT007 degradation under gastric acidic pH was not a major factor controlling oral bioavailability of the drug. Instead, low solubility at a higher pH might have contributed to the observed low bioavailability. The findings illustrate that optimizing oral bioavailability for OJT007 requires formulation strategies that simultaneously address solubility at intestinal pH and stability in the stomach.
Keywords:
pH-dependent solubility
Oral bioavailability
Pharmacokinetics
Antileishmanial
LC MS/MS
Methionine aminopeptidase inhibitor
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