Gastroduodenal Behavior of Suspension, Solution, and Tablet Formulations of Delaviridine (U-90152) in an Attempt to Understand This Reverse Transcriptase Inhibitors Solubilization and Supersaturation Characteristics
Dean, Corey R.
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Delaviridine, a non-competitive, reverse transcriptase inhibitor of the HIV virus, is a weak base with a pKa of 4.56 and a water solubility of 0.85 J.1g/ml at the pH of the small intestine (pH = 5 - 6). Because of the low pKa and water solubility, solubilization in the stomach and precipitation in the duodenum was expected. However, in previous work, a solution of U-901525 in propylene glycol administered orally in a duodenally fistulated dog showed extensive supersaturation in the duodenum with -80% of the drug in solution in the duodenal fluid. These results led to the proposal that the extent of stomach solubilization of U-901525 and its failure to undergo extensive precipitation in the duodenum might determine the extent of absorption of delaviridine. An in situ rat intestinal perfusion model showed that the rate of absorption of U-901525 from a supersaturated solution was dramatically enhanced (about 700) over that of the U-90152 free base suspension. This demonstrated greatly enhanced absorption results from in vivo supersaturation of delaviridine. In vitro time dependent solubility studies with the U-901525 tablet in dog gastric fluid (37°C) at pH 1.5, 3, and 6 showed that solubilization of U-90152 increased as the pH decreased, but supersaturation was clearly evidenced only at pH 6. In addition, the U-90152 free base suspension solubility was lower than the tablet. To test whether duodenal supersaturation is highly significant in the absorption of delaviridine, the U-901525 tablet was administered orally to the duodenally fistulated dog at gastric pH's of 1.5, 3, and 6. This study showed that there was a rough correlation between the duodenal pH and the amount of drug in solution, with the concentration of the delaviridine tablet in the dog duodenal fluid being higher at lower stomach pH values. These results indicate that the U-90152S tablet forms a supersaturated solution in the duodenum and the solubility of U-901525 is profoundly influenced by a low stomach pH. It is possible that the variability in stomach pH may explain some of the variability experienced in blood levels seen with the U-901S25 tablet.