Department of Drug Sciences, University of Pavia, Viale Tarameli 12, 27100 Pavia, Italy.
Curr Drug Metab. 2013 Jan;14(1):80-9.
Drug nanocarriers have shown great potential in therapy and as diagnostic probes, e.g. in imaging of cancer and inflammation. Imaging can be applied to localize the carrier or the drug itself in the body and/or tissues. In this particular case it is important that drug molecules have the characteristics for possible detection, e.g. after modification with positron emission tomography compliant radioisotopes, without affecting their pharmacological behavior. In order to easily and efficiently follow the ADME profile of the drug after loaded into nanocarriers, the drug can be radiolabelled with, e.g. 18F-label, in order to assess its biodistribution after enteral and parenteral administration in rats. However, this is only possible if the derivative compound behaves similarly to the parent drug compound. In this study, indomethacin (a poorly water-soluble drug) was chosen as a model compound and aimed to evaluate the physicochemical and biopharmaceutical properties of an analog of indomethacin (IMC), fluoro-indomethacin (F-IMC). Although some of the physicochemical and biopharmaceutical properties of IMC are already known, in order to establish a feasible comparison between IMC and F-IMC, the behavior of the former was also investigated in the same conditions as for F-IMC. In this context, both IMC and F-IMC were thermally and morphologically studied. Furthermore, the following properties were also studied for both compounds: pKa and logP, solubility and dissolution profiles at physiological pH values, and toxicity at different concentrations in Caco-2 cells. Finally, the transport across Caco- 2 monolayers of the IMC and F-IMC at physiological pH range was also investigated. The results obtained showed similar values in pKalogP, solubility, dissolution, cytotoxicity, and permeability for both compounds. Thus, there might be strong evidence that both IMC and F-IMC should have a similar ADME behavior and profiles in vivo. The results provide fundamental tools and ideas for further research with nanocarriers of 18F-IMC.
药物纳米载体在治疗和诊断探针方面显示出巨大的潜力，例如在癌症和炎症的成像中。成像可以用于在体内和/或组织中定位载体或药物本身。在这种特殊情况下，很重要的是药物分子具有可能检测到的特性，例如用符合正电子发射断层扫描的放射性同位素进行修饰后，而不影响其药理学行为。为了在将药物加载到纳米载体后轻松有效地跟踪药物的 ADME 概况，可以用例如 18F 标记物对药物进行放射性标记，以评估其在大鼠口服和静脉给药后的生物分布。然而，只有在衍生化合物的行为与母体药物化合物相似的情况下才有可能。在这项研究中，选择吲哚美辛（一种水溶性差的药物）作为模型化合物，并旨在评估吲哚美辛（IMC）类似物，氟吲哚美辛（F-IMC）的物理化学和生物制药特性。尽管已经了解 IMC 的一些物理化学和生物制药特性，但为了在 IMC 和 F-IMC 之间建立可行的比较，还研究了前者在与 F-IMC 相同条件下的行为。在这种情况下，对 IMC 和 F-IMC 进行了热和形态学研究。此外，还研究了这两种化合物的以下特性：pKa 和 logP、在生理 pH 值下的溶解度和溶解曲线以及在不同浓度下在 Caco-2 细胞中的毒性。最后，还研究了 IMC 和 F-IMC 在生理 pH 范围内穿过 Caco-2 单层的转运情况。得到的结果表明，两种化合物的 pKa 和 logP、溶解度、溶解、细胞毒性和渗透性具有相似的值。因此，有强有力的证据表明，IMC 和 F-IMC 都应该具有相似的体内 ADME 行为和概况。研究结果为进一步研究 18F-IMC 的纳米载体提供了基本工具和思路。
