Watts Alan B, Williams Robert O, Peters Jay I
Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, Austin, TX, USA.
Drug Dev Ind Pharm. 2009 Mar;35(3):259-71. doi: 10.1080/03639040802282904.
Since the discovery of cyclosporine in 1971, calcineurin inhibitors have played a critical role in the therapeutic suppression of the immune response. Patients receiving solid organ transplants rely heavily on these medications to prevent the acute and chronic rejection of allografted tissue. These therapies can prove difficult because of potential toxicity, heightened risk of invasive infection, and erratic oral bioavailability, requiring frequent blood samples for monitoring of systemic levels. Added challenges are presented in immunosuppression of lung transplant patients owing to the increased susceptibility to invasive infection and extensive immune mechanisms inherent in lung tissue. With the introduction of tacrolimus, a more potent calcineurin inhibitor, clinical outcomes of transplants have continued to improve; however, little improvement has been noted in lung transplantation. While very effective upon arrival at the site of action, tacrolimus and cyclosporine present a variety of formulation challenges such as poor solubility, potential systemic toxicity, and extensive first pass metabolism. Initial attempts to improve solubility in both oral and intravenous formulations have resulted in variable drug absorption and increased systemic toxicity, respectfully, creating a need for formulation improvement. Through alternative routes of delivery and novel formulation techniques, researchers have addressed these issues and, in some cases, demonstrated improved clinical outcomes. Through enhanced solubilization, reduction in absorption variability, and more effective drug targeting with reduced systemic levels, improvements in outcomes and overall patient survival in lung and other solid organ transplantation can be expected.
自1971年发现环孢素以来，钙调神经磷酸酶抑制剂在免疫反应的治疗性抑制中发挥了关键作用。接受实体器官移植的患者严重依赖这些药物来预防移植组织的急性和慢性排斥反应。由于潜在的毒性、侵袭性感染风险增加以及口服生物利用度不稳定，这些治疗可能会很困难，需要频繁采集血样来监测全身水平。肺移植患者的免疫抑制面临更多挑战，因为他们对侵袭性感染的易感性增加，且肺组织中存在广泛的免疫机制。随着更有效的钙调神经磷酸酶抑制剂他克莫司的引入，移植的临床结果持续改善；然而，肺移植方面的改善并不明显。虽然他克莫司和环孢素在到达作用部位时非常有效，但它们存在各种制剂方面的挑战，如溶解度差、潜在的全身毒性和广泛的首过代谢。最初改善口服和静脉制剂溶解度的尝试分别导致了药物吸收的变化和全身毒性的增加，因此需要改进制剂。通过替代给药途径和新型制剂技术，研究人员已经解决了这些问题，并且在某些情况下，临床结果得到了改善。通过增强溶解、减少吸收变异性以及在降低全身水平的情况下更有效地靶向药物，可以预期肺和其他实体器官移植的结果和患者总体生存率会得到改善。
