最近的研究强调了 ATP 结合盒 (ABC) 转运蛋白的关键作用，包括 P-糖蛋白 (P-gp)、乳腺癌耐药蛋白 (BCRP) 和多药耐药蛋白 4 (MRP4)。限制几种抗病毒药物的大脑分布。在本研究中，我们研究了这些转运蛋白的抑制是否会增加血脑屏障（BBB）对更昔洛韦的通透性。开发了一种微透析和高效液相色谱方法来监测脑间质液中未结合的更昔洛韦的浓度和血浆，使用或不使用 ABC 转运蛋白抑制剂。药代动力学参数，包括从时间0到最后可测量分析物浓度的血浆浓度-时间曲线下面积（AUC0-t，血浆）、从时间0到最后可测量分析物浓度的脑间质液浓度-时间曲线下面积计算最后可测量的分析物浓度（AUC0-t，脑）和未结合的脑与血浆浓度比（Kp，uu，脑）。平均AUC0-t，血浆，AUC0-t，脑和Kp，uu单独接受更昔洛韦（30 mg/kg，腹腔注射）的大鼠脑部分别为 1090 min·μg/mL、150 min·μg/mL 和 14%。施用tariquidar（P-gp抑制剂）、Ko143（BCRP抑制剂）或MK-571（MRP4抑制剂）后，更昔洛韦的Kp,uu,脑增加至31±2.1%、26±1.3%，和 32 ± 2.0%，分别。本研究的结果表明 ABC 转运蛋白 P-gp、BCRP 和 MRP4 介导更昔洛韦在 BBB 的流出，并且抑制这些转运蛋白可促进更昔洛韦渗透 BBB。© 2024 年。作者获得 Springer Nature Switzerland AG 的独家许可。

Recent studies have highlighted the key role of the ATP-binding cassette (ABC) transporters, including the P-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and the multi-drug resistance protein 4 (MRP4) in limiting the brain distribution of several antiviral agents. In this study, we investigated whether the inhibition of these transporters increases the permeability of the blood-brain barrier (BBB) to ganciclovir.A microdialysis and high-performance liquid chromatographic method was developed to monitor the concentrations of unbound ganciclovir in the brain interstitial fluid and plasma, with and without the administration of ABC transporter inhibitors. Pharmacokinetic parameters, including the area under the plasma concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC0-t,plasma), the area under the brain interstitial fluid concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC0-t,brain), and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) were calculated.The mean AUC0-t,plasma, AUC0-t,brain, and Kp,uu,brain in rats who received ganciclovir (30 mg/kg, intraperitoneal) alone were 1090 min·µg/mL, 150 min·µg/mL, and 14%, respectively. After the administration of tariquidar (inhibitor of P-gp), Ko143 (inhibitor of BCRP), or MK-571 (inhibitor of MRP4), the Kp,uu,brain of ganciclovir increased to 31 ± 2.1%, 26 ± 1.3%, and 32 ± 2.0%, respectively.The findings of this study suggest that ABC transporters P-gp, BCRP, and MRP4 mediate the efflux of ganciclovir at the BBB and that the inhibition of these transporters facilitates the penetration of the BBB by ganciclovir.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.