In vitro and in situ permeability of a 'second generation' hydroxypyridinone oral iron chelator:: Correlation with physico-chemical properties and oral activity

Purpose. The irt vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl)-2-hydroxyphenyl-methyl-1H-pyridin-4-one), a novel oral iron chelator, is described. The predictive power of these data in assessing intestinal absorption in man is described. Methods. Caco-2 epithelial monolayer and in situ rat jejunum perfusion intestinal permeability models were utilized. In vivo iron excretion and preliminary animal pharmacokinetic experiments were described. Ionization constants and octanol/aqueous partition coefficients were measured potentiometrically. Solubilities and intrinsic dissolution rates were determined using standard procedures. Results. Caco-2 cell (P-app similar to 0.25 x 10(-6) cm.s(-1)) and rat jejunum (P-w similar to 0.4) permeabilities of CGP 65015 were determined. The log D(pH 7.4) of CGP 65015 was 0.58 and its aqueous solubility was < 0.5 mg.ml(-1) (pH 3-9). The intrinsic dissolution rate of CGP 65015 in USP simulated intestinal fluid was 0.012 mg.min(-1).cm(-2). CGP 65015 promotes iron excretion effectively and dose dependently in animals. Conclusions, Caco-2 and rat intestinal permeabilities predict incomplete oral absorption of CGP 650 15 in man. Preliminary rat pharmacokinetics support this. Physico-chemical data are, also, in line and suggest that CGP 65015 may, in addition, be solubility/dissolution rate limited in vivo. Nevertheless, early animal pharmacological data demonstrate that COP 65015 is a viable oral iron chelator candidate.