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L-365,260, a specific and potent nonpeptide antagonist of the CCKB receptor, is under investigation for its potential utility in the treatment of anxiety and panic disorders. This drug has a very low aqueous solubility (< 2 micrograms mL-1). When L-365,260 was given orally as a suspension in 0.5% methylcellulose (5 mg kg-1), the absorption was rapid but incomplete. The peak concentrations occurred in about 30-40 min, and the bioavailability was 8.6% for the dog and 13.6% for the rat. The poor bioavailability could be attributed to poor absorption or extensive first-pass metabolism. By comparing the drug concentrations in the systemic circulation during portal and femoral (or cephalic) vein infusion, the hepatic first-pass metabolism was estimated to be 0.30 for the rat and 0.14 for the dog, suggesting that first-pass metabolism is not the main reason for the low bioavailability of the drug in rats and dogs. The limited bioavailability is, therefore, more likely due to its poor absorption as a result of its poor aqueous solubility and slow dissolution rate. However, while the absorption was substantially improved when the drug was given orally as a solution in PEG 600 solution, the bioavailability increased threefold to fourfold in rats and sixfold to sevenfold in dogs. Although the underlying mechanism for the improved absorption is unknown, PEG 600 may have exerted a cosolubilizing effect which enhances the dissolution rate of L-365,260 in the GI tract, resulting in better absorption. Kinetic analysis by a deconvolution technique revealed that PEG 600 increased both the extent and rate of absorption. These results are consistent with the notion that absorption of L-365,260 is rate limited by its dissolution rate. The data from these animal studies provides valuable information in selecting the formulation for clinical trials.

In vitro dissolution profile testing of 12 generic 6-propyl-2-thiouracil (PTU) formulations indicated significant differences in their solubilities in water and in 0.1N hydrochloric acid. Two products, representing the extremes of solubility, were subsequently tested for bioavailability. Bioavailability data from euthyroid, hyperthyroid, and hypothyroid beagle dogs indicated that the rate of PTU absorption varied appreciably between the two generic products studied. These results were consistent with the in vitro dissolution data. Comparisons of the pharmacokinetic parameters obtained for the euthyroid beagle dog to those reported for euthyroid man12 indicated that the beagle dog is an adequate model for PTU disposition in man. These combined results suggest that all generic formulations of PTU are not the same and that the most soluble product may be desirable in situations where rapid absorption is important, such as thyroid storm.