P-Glycoproten as a Molecular Target of Pharmacokinetic Studies for the Reversal of Multidrug Resistance

多药耐药（MDR）是癌症化疗的主要障碍。多药耐药的一个重要机制是p -糖蛋白（P-gp）主动将抗癌药物排出细胞外，降低其在细胞内的浓度，从而产生对多种药物的耐药性。调节P-gp可逆转耐多药，改善肿瘤化疗的预后。SDZ PSC 833是一种非免疫抑制的环孢素衍生物，其逆转多药耐药的效力是环孢素a的5- 10倍。这可能是因为PSC 833不通过人P-gp转运，并且比cs - a - 2更疏水。耐多药转染细胞的转运活性与P-gp蛋白的表达水平密切相关。多西紫杉醇是一种新型抗癌药物，它是通过p -gp转运的底物。伊曲康唑抑制P-gp介导的地高辛转运，提示临床上重要的地高辛-伊曲康唑相互作用机制。伊曲康唑还逆转了P-gp表达细胞对长春花碱的敏感性。各种Ca^<2+>拮抗剂对地高辛经P-gp转运的抑制作用与Ca^<2+>拮抗剂的分子量有关。

Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. One of important mechanisms of MDR is P-glycoprotein (P-gp) which actively expels anticancer drugs out of the cells and decreased their intracellular concentration, resulting in the resistance aganinst multiple agents. Modulation of P-gp can reverse the MDR and many improve outcome of cancer chemotherapy.1. SDZ PSC 833, a non-immunosuppressive cyclosporin derivative, was 5-to 10-fold more potent to reverse multidrug resistance compared to cyclosporin A.This is probably because PSC 833 is not transported by human P-gp and is more hydrophobic than Cs-A.2. Transport activity in the MDR-transfected cells was well correlated with the expression level of P-gp protein.3. Docetaxl, a new anticancer agent, was a substrate transported by P-gp.4. Itraconazole inhibited the P-gp mediated transport of digoxin, suggesting a mechanism of clinically important digoxin-itraconazole interaction. Itraconazole also reversed sensitivity to vinblastine in the P-gp expressed cells.5. Inhibitory effect of various Ca^<2+> antagonists on digoxin transport via P-gp was related to the molecular weight of Ca^<2+> antagonists.