Table V-Correlation Coefficients of Bioavailability Parameters Between Humans and Beagles Beagle Human r c0.5' c1 c7 0.789 0.505 C1 c, 0.678 c 3 0.448 Cmax Cmax 0.388 tmax 0.711 2E2* A uc47.5 0.306 Ct shows the plasma or serum concentration at time t .
in beagles contrary to its lower absorption in humans. Considering the insignificant effects of the volume of water on the bioavailability, the ultramicrosize formulation discrepancy may be attributed to the physiological differences in the GI tract. None of the in uitro dissolution methods indicated such a superiority of the ultramicrosize formulation in beagles. These findings suggest that this formulation may disintegrate into the original ultramicrosize particulate state of the drug and allow rapid dissolution in the GI tract in beagles beyond the expectation from the in uitro dissolution findings. The't,,,, values in beagles for different formulations were smaller than those in humans (Fig. 4). This suggests rapid transition of the drug to the absorption site, namely, fast gastric emptying of the drug in beagles. The good bioavailability of the ultramicrosize formulation may be related to the rapid gastric emptying of the drug which leads to dissolution of the drug in the small intestinal tract.
Formulation D provided higher Cmax and plasma levels a t earlier sampling times than Formulation C as observed in the human test. The in uitro dissolution rate of the drug from Formulation D was enhanced over that from Formulation C by pretreatment with plastic beads. These findings suggest that in beagles and humans there is a strong intensive deaggregation action on the particles or aggregates of the drug during their transition into the GI tract.
Although there was no significant difference in AUC, values among the formulations in humans, the AUC24 (considered as AUC,) of Formulations C and D were significantly lower than that of Formulation A in beagles. This suggests their incomplete dissolution during passage through the GI tract and also suggests the short absorption site and/or fast transition of the drug in the GI tract in beagles as previously shown for the bioavailability of diazepam in beagles (3).
Although the in uiuo findings of the ultramicrosize formulation in beagles did not agree with those in humans, the bioavailabilities of the microsize formulations showed good agreement. Considering this, beagles may serve as a useful animal model for bioavailability studies of certain griseofulvin tablet formulations, but not ultramicrosize ones.
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