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

• Published in: Pharmaceutical research Vol. 16; no. 3; pp. 434 - 440
• Main Authors: LOWTHER, N, FOX, R, FALLER, B, NICK, H, YI JIN, SERGEJEW, T, HIRSCHBERG, Y, OBERLE, R, DONNELLY, H
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01-03-1999; Springer Nature B.V
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Caco-2 Cells; Callithrix; Carbon Radioisotopes; General and cellular metabolism. Vitamins; Humans; In Vitro Techniques; Intestinal Absorption; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacokinetics; Jejunum - metabolism; Male; Mannitol - metabolism; Medical sciences; Perfusion; Permeability; Pharmacology. Drug treatments; Pyridines - chemistry; Pyridines - pharmacokinetics; Rats; Rats, Inbred F344; Human; Rat; Digestive system; Biological transport; Rodentia; Gut; Solubility; Oral administration; Lipophily; Iron; Bioavailability; Permeability; In vitro; In vivo; Vertebrata; Mammalia; Absorption; Animal; Established cell line; Chelating agent; Pharmacokinetics; Tumor cell; Physicochemical properties
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1018886005136

The in vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl)-2-hydroxyphenyl-methyl-1H-pyridin-4-on e), a novel oral iron chelator, is described. The predictive power of these data in assessing intestinal absorption in man is described.
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.
Caco-2 cell (Papp approximately 0.25 x 10(-6) cm x s(-1)) and rat jejunum (Pw approximately 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 x ml(-1) (pH 3-9). The intrinsic dissolution rate of CGP 65015 in USP simulated intestinal fluid was 0.012 mg x min(-1) x cm(-2). CGP 65015 promotes iron excretion effectively and dose dependently in animals.
Caco-2 and rat intestinal permeabilities predict incomplete oral absorption of CGP 65015 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 CGP 65015 is a viable oral iron chelator candidate.