Lowther N, Tomlinson B, Fox R, Faller B, Sergejew T, Donnelly H
Pharmaceutical and Analytical Development, Ciba Pharmaceuticals (now Novartis Horsham Research Centre), Wimblehurst Road, Horsham, West Sussex RH12 4AB, England.
J Pharm Sci. 1998 Sep;87(9):1041-5. doi: 10.1021/js980191s.
This study describes the transport of CGP 75254A, a novel oral iron chelator, across Caco-2 cells in an attempt to model intestinal epithelial cell permeability in man. CGP 75254A was dosed to the apical side of Caco-2 cell monolayers, together with [14C]mannitol as an internal permeability standard. The apparent permeability (Papp) was calculated from the cumulative appearance of drug in the basolateral fluid with time. The [14C]mannitol Papp indicated that the Caco-2 monolayers remained intact and that the iron chelator was not toxic to the cells. Permeabilities of CGP 75254A were compared with the Caco-2 permeabilities of compounds of known absorption in man. The results predict that absorption of CGP 75254A is likely to be virtually complete at pH values between 5.5 and 7.0. However, at pH 8.0 permeability is predicted as negligible. Cell permeability data are in full accordance with key physicochemical properties of CGP 75254A and suggest that the drug is passively absorbed. The results, which suggest likely quantitative absorption in vivo, are supported by preliminary pharmacological experiments in marmosets.
本研究描述了新型口服铁螯合剂CGP 75254A透过Caco-2细胞的过程，旨在模拟人体肠道上皮细胞的通透性。将CGP 75254A加入到Caco-2细胞单层的顶端侧，并加入[14C]甘露醇作为内部通透性标准。根据药物在基底外侧液体中随时间的累积出现量计算表观通透性（Papp）。[14C]甘露醇的Papp表明Caco-2细胞单层保持完整，且铁螯合剂对细胞无毒。将CGP 75254A的通透性与人体中已知吸收情况的化合物的Caco-2通透性进行比较。结果预测，在pH值为5.5至7.0之间时，CGP 75254A的吸收可能几乎是完全的。然而，在pH 8.0时，预测其通透性可忽略不计。细胞通透性数据与CGP 75254A的关键物理化学性质完全一致，表明该药物是被动吸收的。在狨猴身上进行的初步药理学实验支持了这些结果，这些结果表明该药物在体内可能会有定量吸收。
