The effect of pH stability and aqueous solubility on the oral bioavailability of a novel antileishmanial agent.

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 (C