Gupta Anshul, Dai Yang, Vethanayagam R Robert, Hebert Mary F, Thummel Kenneth E, Unadkat Jashvant D, Ross Douglas D, Mao Qingcheng
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, 98195-7610, USA.
Cancer Chemother Pharmacol. 2006 Sep;58(3):374-83. doi: 10.1007/s00280-005-0173-6. Epub 2006 Jan 11.
Several studies have demonstrated significant interactions between immunosuppressants (e.g., cyclosporin A) and chemotherapeutic drugs that are BCRP substrates (e.g., irinotecan), resulting in increased bioavailability and reduced clearance of these agents. One possible mechanism underlying this observation is that the immunosuppressants modulate the pharmacokinetics of these drugs by inhibiting BCRP. Therefore, the aim of this study was to determine whether the immunosuppressants cyclosporin A, tacrolimus and sirolimus are inhibitors and/or substrates of BCRP.
First, the effect of the immunosuppressants on BCRP efflux activity in BCRP-expressing HEK cells was measured by flow cytometry.
Cyclosporin A, tacrolimus and sirolimus significantly inhibited BCRP-mediated efflux of pheophorbide A, mitoxantrone and BODIPY-prazosin. The EC(50) values of cyclosporin A, tacrolimus and sirolimus for inhibition of BCRP-mediated pheophorbide A efflux were 4.3 +/- 1.9 microM, 3.6 +/- 1.8 microM and 1.9 +/- 0.4 microM, respectively. Cyclosporin A, tacrolimus and sirolimus also effectively reversed resistance of HEK cells to topotecan and mitoxantrone conferred by BCRP. When direct efflux of cyclosporin A, tacrolimus and sirolimus was measured, these compounds were found not to be transported by BCRP. Consistent with this finding, BCRP did not confer resistance to the immunosuppressants in HEK cells.
These results indicate that cyclosporin A, tacrolimus and sirolimus are effective inhibitors but not substrates of BCRP. These findings could explain the altered pharmacokinetics of BCRP substrate drugs when co-administered with the immunosuppressants and suggest that pharmacokinetic modulation by the immunosuppressants may improve the therapeutic outcome of these drugs.
多项研究已证实免疫抑制剂（如环孢素A）与作为乳腺癌耐药蛋白（BCRP）底物的化疗药物（如伊立替康）之间存在显著相互作用，导致这些药物的生物利用度增加和清除率降低。这一观察结果的一种可能机制是免疫抑制剂通过抑制BCRP来调节这些药物的药代动力学。因此，本研究的目的是确定免疫抑制剂环孢素A、他克莫司和西罗莫司是否为BCRP的抑制剂和/或底物。
首先，通过流式细胞术测量免疫抑制剂对表达BCRP的人胚肾（HEK）细胞中BCRP外排活性的影响。
环孢素A、他克莫司和西罗莫司显著抑制BCRP介导的脱镁叶绿酸A、米托蒽醌和硼替佐辛的外排。环孢素A、他克莫司和西罗莫司抑制BCRP介导的脱镁叶绿酸A外排的半数有效浓度（EC50）值分别为4.3±1.9微摩尔/升、3.6±1.8微摩尔/升和1.9±0.4微摩尔/升。环孢素A、他克莫司和西罗莫司还有效逆转了BCRP赋予HEK细胞对拓扑替康和米托蒽醌的耐药性。当测量环孢素A、他克莫司和西罗莫司的直接外排时，发现这些化合物不能被BCRP转运。与这一发现一致，BCRP未赋予HEK细胞对免疫抑制剂的耐药性。
这些结果表明环孢素A、他克莫司和西罗莫司是有效的BCRP抑制剂，但不是其底物。这些发现可以解释与免疫抑制剂合用时BCRP底物药物药代动力学的改变，并表明免疫抑制剂的药代动力学调节可能改善这些药物的治疗效果。
