Abstract
ABSTRACTIntroductionSolubility/dissolution and permeability are essential determinants of gastrointestinal absorption of drugs.In vitroaqueous solubility (S) and apparent permeability (Papp) are commonly used as measurements and predictors ofin vivofraction absorbed (fa) and BCS-classing in humans. The objective of this study was to explore the relationships betweenin vitroaqueous S and Dose number (Do) andin vivofaandin vitroPappandin vivofaand the predictive power ofin vitroaqueous S, Doand Papp.MethodsIn vitroandin vivodata were taken from studies in the literature and correlated.In vitroS data were produced in various laboratories and with different methodologies.In vitroPappdata were produced using Caco-2 and MDCK cells in various laboratories and Caco-2 and RRCK cells in one laboratory each. Dowas estimated as oral dose / (S • 250 mL).Results452 S data and 1480 Pappdata were found and used. There was no correlation (R2=0.0) betweenin vitrolog S and Dovs in vivofa, not even at S<1 mg/L or not for compounds with <90 % and <30 %in vivofa. A R2of 0.43 was found between log Caco-2 Pappandin vivofa. The corresponding R2for Caco-2 from one laboratory was 0.65. The interlaboratory R2for the Caco-2 model was 0.48. R2-estimates for Caco-2vsMDCK and Caco-2vsRRCK Pappwere 0.23 and 0.21, respectively.Discussion and ConclusionAqueous S appears to have no predictive value ofin vivofain 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 Pappexplains about half of the variance ofin vivofain humans. The poor correlations found between Caco-2 and the two other Papp-models (MDCK and RRCK) demonstrate considerable methodological differences. The unexplained variance does not appear to be explained by S and dose, but rather byin vitro-in vivodifference in permeability and poor/absent relationship betweenin vitroS andin vivodissolution potential.
Publisher
Cold Spring Harbor Laboratory