Brillault J, Tewes F, Couet W, Olivier J C
Inserm U1070, Pôle Biologie Santé, 1 Rue Georges Bonnet, Poitiers, France; Université de Poitiers, UFR de Médecine et Pharmacie, 15 Rue de l'Hôtel Dieu, Poitiers, France.
Inserm U1070, Pôle Biologie Santé, 1 Rue Georges Bonnet, Poitiers, France; Université de Poitiers, UFR de Médecine et Pharmacie, 15 Rue de l'Hôtel Dieu, Poitiers, France; CHU de Poitiers, Service de Toxicologie-Pharmacocinétique, 2 rue de la Milétrie, Poitiers, France.
Eur J Pharm Sci. 2017 Jan 15;97:92-98. doi: 10.1016/j.ejps.2016.11.011. Epub 2016 Nov 15.
Pulmonary delivery of fluoroquinolones (FQs) is an interesting approach to treat lung infections as it may lead to high local concentrations while minimizing systemic exposure. However, FQs have a rapid diffusion through the lung epithelium giving the pulmonary route no advantage compared to the oral route. Interactions between FQs and metal cations form complexes which limit the diffusion through the epithelial barrier and would reduce the absorption of FQs and maintain high concentrations in the lung. The effects of this complexation depend on the FQ and the metal cations and optimum partners should be selected through in vitro experiments prior to aerosol drug formulation. In this study, CIP was chosen as a representative FQ and 5 cations (Ca, Mg, Zn, Al, Cu) were selected to study the complexation and its effects on permeability, antimicrobial efficacy and cell toxicity. The results showed that the apparent association constants between CIP and cations ranked with the descending order: Cu>Al>Zn>Mg>Ca. When a target of 80% complexation was reached with the adequate concentrations of cations, the CIP permeability through the Calu-3 lung epithelial cells was decreased of 50%. Toxicity of the CIP on the Calu-3 cells, with an EC50 evaluated at 7μM, was not significantly affected by the presence of the cations. The minimum inhibitory concentration of CIP for Pseudomonas aeruginosa was not affected or slightly increased in the range of cation concentrations tested, except for Mg. In conclusion, permeability was the main parameter that was affected by the metal cation complexation while cell toxicity and antimicrobial activity were not or slightly modified. Cu, with the highest apparent constant of association and with no effect on cell toxicity and antimicrobial activity of the CIP, appeared as a promising cation for the development of a controlled-permeability formulation of CIP for lung treatment.
氟喹诺酮类药物（FQs）的肺部给药是治疗肺部感染的一种有趣方法，因为它可能导致高局部浓度，同时将全身暴露降至最低。然而，FQs可快速穿过肺上皮细胞，与口服途径相比，肺部给药途径并无优势。FQs与金属阳离子之间的相互作用形成复合物，限制了其通过上皮屏障的扩散，会减少FQs的吸收并在肺部维持高浓度。这种络合作用的效果取决于FQs和金属阳离子，在进行气雾剂药物制剂之前，应通过体外实验选择最佳的配对组合。在本研究中，选择环丙沙星（CIP）作为代表性的FQs，并选择5种阳离子（钙、镁、锌、铝、铜）来研究络合作用及其对通透性、抗菌效果和细胞毒性的影响。结果表明，CIP与阳离子之间的表观缔合常数按降序排列为：铜>铝>锌>镁>钙。当用适当浓度的阳离子达到80%的络合目标时，CIP通过Calu-3肺上皮细胞的通透性降低了50%。阳离子的存在对CIP对Calu-3细胞的毒性（EC50评估为7μM）没有显著影响。除镁外，在所测试的阳离子浓度范围内，CIP对铜绿假单胞菌的最低抑菌浓度未受影响或略有增加。总之，通透性是受金属阳离子络合作用影响的主要参数，而细胞毒性和抗菌活性未受影响或略有改变。铜具有最高的表观缔合常数，且对CIP的细胞毒性和抗菌活性没有影响，似乎是开发用于肺部治疗的CIP控释制剂的一种有前景的阳离子。
