Valspodar is a potent inhibitor of P-glycoprotein (P-gp) widely used in preclinical and clinical studies [1].
P-gp is a transmembrane glycoprotein which is located on cell membrane. P-gp distributes extensively and is expressed in certain cell types primarily containing liver, colon, kidney and pancreas. It also is known as multidrug resistance protein 1 (MDR1) which is pumps foreign substances out of cells. P-gp decreases the net uptake of cytotoxic drugs into the cells and mediats the efflux of these agents out of the cells, which is ATP-dependent. P-gp also overexpress in some cancer cells. P-gp plays an important role in mediating resistance to anticancer drugs and decreasing drug accumulation in multidrug-resistant cancer cells.[1]
Valspodar can reverse the resistance to mitoxantrane which is due to the expression of P-gp. The IC50 of mitoxantrane decreased from 1.6 ± 0.13 μM to 0.4 ± 0.02
μM in MDA-MB-435mdr cells pretreated with 3 mg/ml PSC. Valspodar increase the mitoxantrane intracellular accumulation by decreasing drug efflux and increasing mitoxantrone net uptake in cells.[1] The cytotoxicity was significant greater in T47D/TAMR-6 cells treated with doxorubicin and valspodar than doxorubicin only. Co-encapsulation of doxorubicin and valspodar presents a promising anticancer effect.[2] Valspodar was rapid absorpted and reachs the peak within 2 hnafter an oral dose. Valspodar showed properties of wide distribution, low hepatic extraction and mean bioavailability of 42.8% in rat.[3]
References:
[1]. Shen F, Bailey BJ, Chu S, Bence AK, Xue X, Erickson P, Safa AR, Beck WT, Erickson LC: Dynamic assessment of mitoxantrone resistance and modulation of multidrug resistance by valspodar (PSC833) in multidrug resistance human cancer cells. J Pharmacol Exp Ther 2009, 330(2):423-429.
[2]. Bajelan E, Haeri A, Vali AM, Ostad SN, Dadashzadeh S: Co-delivery of doxorubicin and PSC 833 (Valspodar) by stealth nanoliposomes for efficient overcoming of multidrug resistance. J Pharm Pharm Sci 2012, 15(4):568-582.
[3]. Binkhathlan Z, Hamdy DA, Brocks DR, Lavasanifar A: Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat. Xenobiotica 2010, 40(1):55-61.
Valspodar 是一种有效的 P-糖蛋白 (P-gp) 抑制剂，广泛用于临床前和临床研究 [1]。
P-gp 是一种位于细胞膜上的跨膜糖蛋白。 P-gp 广泛分布并在某些细胞类型中表达，主要包括肝脏、结肠、肾脏和胰腺。它也被称为多药耐药蛋白 1 (MDR1)，可将异物泵出细胞。 P-gp 减少细胞毒性药物对细胞的净吸收，并介导这些药物流出细胞，这是 ATP 依赖性的。 P-gp 也在一些癌细胞中过表达。 P-gp 在介导抗癌药物耐药和减少多药耐药癌细胞中的药物积累方面发挥重要作用[1]。
Valspodar可以逆转由于P-gp的表达而引起的对mitoxantrane的抗性。米托蒽醌的IC50从1.6 ±下降； 0.13 μM 到 0.4 ±在用 3 mg/ml PSC 预处理的 MDA-MB-435mdr 细胞中为 0.02
μM。 Valspodar 通过减少药物流出和增加细胞中的米托蒽醌净摄取来增加米托蒽醌的细胞内积累。 [1]用多柔比星和缬司泊达处理的 T47D/TAMR-6 细胞的细胞毒性明显高于仅用多柔比星处理的细胞毒性。多柔比星和缬司泊达的共包封具有良好的抗癌作用。 [2] Valspodar 被迅速吸收并达到 ； the peak within 口服后 2 次。 Valspodar 显示出分布广泛、肝脏提取率低和大鼠平均生物利用度为 42.8% 的特性。 [3]