Lowther N, Fox R, Faller B, Nick H, Jin Y, Sergejew T, Hirschberg Y, Oberle R, Donnelly H
Pharmaceutical and Analytical Development, Novartis Horsham Research Centre, West Sussex, United Kingdom.
Pharm Res. 1999 Mar;16(3):434-40. 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.
描述新型口服铁螯合剂CGP 65015（(+)-3-羟基-1-(2-羟乙基)-2-羟基苯基-甲基-1H-吡啶-4-酮）的体外和原位转运情况。阐述这些数据在评估人体肠道吸收方面的预测能力。
采用Caco-2上皮单层和原位大鼠空肠灌注肠道通透性模型。描述了体内铁排泄及初步动物药代动力学实验。用电位滴定法测量电离常数和正辛醇/水分配系数。使用标准程序测定溶解度和固有溶解速率。
测定了CGP 65015在Caco-2细胞（表观渗透系数约为0.25×10⁻⁶ cm·s⁻¹）和大鼠空肠（肠壁渗透系数约为0.4）中的通透性。CGP 65015在pH 7.4时的log D值为0.58，其水溶性在pH 3 - 9时<0.5 mg·ml⁻¹。CGP 65015在USP模拟肠液中的固有溶解速率为0.012 mg·min⁻¹·cm⁻²。CGP 65015在动物体内能有效且剂量依赖性地促进铁排泄。
Caco-2细胞和大鼠肠道通透性预测CGP 65015在人体口服吸收不完全。大鼠初步药代动力学数据支持这一点。物理化学数据也相符，表明CGP 65015在体内可能还受溶解度/溶解速率限制。然而，早期动物药理学数据表明CGP 65015是一种可行的口服铁螯合剂候选物。
