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


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 (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.


CONCLUSIONS
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.
Lowther
N
N
Pharmaceutical and Analytical Development, Novartis Horsham Research Centre, West Sussex, United Kingdom. nicholas.lowther@pharma.novartis.com
Fox
R
R
Faller
B
B
Nick
H
H
Jin
Y
Y
Sergejew
T
T
Hirschberg
Y
Y
Oberle
R
R
Donnelly
H
H
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002144:Callithrix; D002250:Carbon Radioisotopes; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007502:Iron Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000378:metabolism; D010477:Perfusion; D010539:Permeability; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344
C119560:CGP 65015; D002250:Carbon Radioisotopes; D007502:Iron Chelating Agents; D011725:Pyridines; D008353:Mannitol