Didier A, Loor F
Immunology Laboratory, Strasbourg 1 University, Illkirch, France.
Anticancer Drugs. 1996 Sep;7(7):745-51. doi: 10.1097/00001813-199609000-00005.
Among the compounds endowed with the capacity to reverse the P-glycoprotein (Pgp)-mediated multidrug resistance of cancer cells, a powerful agent was found to be the cyclosporin D derivative SDZ PSC 833. After in vivo treatment with SDZ PSC 833, mice showed a decreased tolerability to cyclosporin A (CsA), but also to ivermectin, a widely used polycyclic lactone pesticide of Streptomyces avermitilis origin. The sequels were suggestive of CsA- or ivermectin-induced central nervous system dysfunction; they were interpreted as caused by the neutralization of the Pgp at the blood-brain barrier level, implying that CsA and ivermectin were Pgp substrates. CsA was already known to display both Pgp substrate and Pgp inhibitor properties. It now appears that ivermectin may also inhibit Pgp function. When compared in short-term assays for Pgp function inhibition, which measure the restoration of the retention of two Pgp probes in multidrug-resistant (MDR) cells to their parental (Par) cell levels, ivermectin appeared only a few fold weaker that SDZ PSC 833 in the case of murine monocytic leukemia MDR-P388 cells and nearly as active as SDZ PSC 833 in the case of human lymphocytic leukemia MDR-CEM cells. Therefore, like CsA or FK-506, ivermectin may also be a substrate and an inhibitor of Pgp.
在具有逆转P-糖蛋白（Pgp）介导的癌细胞多药耐药能力的化合物中，发现一种强效药物是环孢菌素D衍生物SDZ PSC 833。用SDZ PSC 833进行体内治疗后，小鼠对环孢菌素A（CsA）以及伊维菌素（一种广泛使用的源自阿维链霉菌的多环内酯类农药）的耐受性降低。这些后果提示CsA或伊维菌素诱导的中枢神经系统功能障碍；它们被解释为是由于血脑屏障水平上Pgp的中和作用所致，这意味着CsA和伊维菌素是Pgp底物。CsA已知具有Pgp底物和Pgp抑制剂的特性。现在看来，伊维菌素也可能抑制Pgp功能。在短期Pgp功能抑制试验中进行比较时，这些试验测量两种Pgp探针在多药耐药（MDR）细胞中的保留恢复到其亲本（Par）细胞水平的情况，在小鼠单核细胞白血病MDR-P388细胞中，伊维菌素的活性仅比SDZ PSC 833弱几倍，而在人淋巴细胞白血病MDR-CEM细胞中，其活性几乎与SDZ PSC 833一样。因此，与CsA或FK-506一样，伊维菌素也可能是Pgp的底物和抑制剂。
