Exploring Relationships Between In Vitro Aqueous Solubility and Permeability and In Vivo Fraction Absorbed
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Introduction
Solubility/dissolution and permeability are essential determinants of gastrointestinal absorption of drugs. In vitro aqueous solubility (S) and apparent permeability (P app ) are commonly used as measurements and predictors of in vivo fraction absorbed (f a ) and BCS-classing in humans. The objective of this study was to explore the relationships between in vitro aqueous S and Dose number (D o ) and in vivo f a and in vitro P app and in vivo f a and the predictive power of in vitro aqueous S, D o and P app .
Methods
In vitro and in vivo data were taken from studies in the literature and correlated. In vitro S data were produced in various laboratories and with different methodologies. In vitro P app data were produced using Caco-2 and MDCK cells in various laboratories and Caco-2 and RRCK cells in one laboratory each. D o was estimated as oral dose / (S • 250 mL).
Results
452 S data and 1480 P app data were found and used. There was no correlation (R 2 =0.0) between in vitro log S and D o vs in vivo f a , not even at S<1 mg/L or not for compounds with <90 % and <30 % in vivo f a . A R 2 of 0.43 was found between log Caco-2 P app and in vivo f a . The corresponding R 2 for Caco-2 from one laboratory was 0.65. The interlaboratory R 2 for the Caco-2 model was 0.48. R 2 -estimates for Caco-2 vs MDCK and Caco-2 vs RRCK P app were 0.23 and 0.21, respectively.
Discussion and Conclusion
Aqueous S appears to have no predictive value of in vivo f a in humans, not even at low S or after correction for dose. The shows that one should not base human biopharmaceutical predictions based on aqueous S. Log Caco-2 P app explains about half of the variance of in vivo f a in humans. The poor correlations found between Caco-2 and the two other P app -models (MDCK and RRCK) demonstrate considerable methodological differences. The unexplained variance does not appear to be explained by S and dose, but rather by in vitro-in vivo difference in permeability and poor/absent relationship between in vitro S and in vivo dissolution potential.
