Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, PR China.
Mol Pharm. 2011 Oct 3;8(5):1629-40. doi: 10.1021/mp100412z. Epub 2011 Aug 31.
Aerosol glucocorticoid medications have become more and more important in treating BA (bronchial asthma). Although these agents are dosed to directly target airway inflammation, adrenocortical suppression and other systematic effects are still seen. To tackle this problem in a novel way, two L-carnitine ester derivatives of prednisolone (as the model drug), namely, PDC and PDSC, were synthesized to increase the absorption of prednisolone across the human bronchial epithelial BEAS-2B cells by the organic cation/carnitine transporter OCTN2 (SLC22A5) and then to slowly and intracellularly release prednisolone. The transport of prednisolone, PDC and PDSC into the human bronchial epithelial BEAS-2B cells was in the order PDSC > prednisolone > PDC at 37 °C. It was found that PDSC displayed 1.79-fold increase of uptake compared to prednisolone. Transport of PDSC by BEAS-2B was temperature-, time-, and Na(+)-dependent and saturable, with an apparent K(m) value of 329.74 μM, suggesting the involvement of carrier-mediated uptake. An RT-PCR study showed that organic cation/carnitine transporters OCTN1 and OCTN2 are expressed in BEAS-2B cells, but little in HEK293T cells. The order of uptake by HEK293T was prednisolone > PDC > PDSC. In addition, the inhibitory effects of organic cations such as L-carnitine, ergothioneine, TEA(+) and ipratropium on PDSC uptake in BEAS-2B cells were in the order L-carnitine > ipratropium > TEA(+) > ergothioneine, whereas their inhibitory effects on PDSC uptake in HEK293T cells were negligible. Finally, in vitro LPS-induced IL-6 production from BEAS-2B was more and longer suppressed by PDSC than prednisolone and PDC. All of these results suggested PDSC may be an attractive candidate for asthma treatment.
吸入性糖皮质激素药物在治疗 BA（支气管哮喘）方面变得越来越重要。尽管这些药物的剂量旨在直接针对气道炎症，但仍会出现肾上腺皮质抑制和其他全身效应。为了以新颖的方式解决这个问题，我们合成了两种泼尼松龙的 L-肉碱酯衍生物（作为模型药物），即 PDC 和 PDSC，以通过有机阳离子/肉碱转运体 OCTN2（SLC22A5）增加泼尼松龙在人支气管上皮 BEAS-2B 细胞中的吸收，然后缓慢地将泼尼松龙在细胞内释放。在 37°C 时，泼尼松龙、PDC 和 PDSC 进入人支气管上皮 BEAS-2B 细胞的转运顺序为 PDSC > 泼尼松龙 > PDC。结果发现，与泼尼松龙相比，PDSC 的摄取量增加了 1.79 倍。BEAS-2B 转运 PDSC 的过程依赖于温度、时间和 Na(+)，且呈饱和状态，表观 K(m) 值为 329.74 μM，表明涉及载体介导的摄取。RT-PCR 研究表明，有机阳离子/肉碱转运体 OCTN1 和 OCTN2 在 BEAS-2B 细胞中表达，但在 HEK293T 细胞中表达很少。HEK293T 摄取的顺序为泼尼松龙 > PDC > PDSC。此外，有机阳离子如 L-肉碱、麦角硫因、TEA(+) 和异丙托溴铵对 BEAS-2B 细胞中 PDSC 摄取的抑制作用顺序为 L-肉碱 > 异丙托溴铵 > TEA(+) > 麦角硫因，而它们对 HEK293T 细胞中 PDSC 摄取的抑制作用可以忽略不计。最后，体外 LPS 诱导的 BEAS-2B 细胞产生的 IL-6 被 PDSC 抑制的程度和时间均大于泼尼松龙和 PDC。所有这些结果表明，PDSC 可能是治疗哮喘的一种有吸引力的候选药物。
