Lemaire M, Bruelisauer A, Guntz P, Sato H
Sandoz Pharma Ltd., Basle, Switzerland.
Cancer Chemother Pharmacol. 1996;38(5):481-6. doi: 10.1007/s002800050515.
This study quantitatively assessed the brain penetration of a potent P-glycoprotein inhibitor, SDZ PSC 833, and its effect on the blood-brain barrier (BBB) permeability (PS) of an anticancer agent, vincristine. At lower doses of SDZ PSC 833 the brain penetration, defined as the brain-to-blood partition coefficient (Kp), was very low in spite of the high lipophilicity of this compound. At higher doses, however, the brain penetration of SDZ PSC 833 was markedly increased. Since the blood pharmacokinetics of SDZ PSC 833 proved to be linear in the dose range studied, these results demonstrated a dose-dependent brain passage of SDZ PSC 833. The brain passage of cyclosporin A was also found to be dose-dependent. However, the potency of SDZ PSC 833 in inhibiting the efflux mechanism at the BBB was higher than that of cyclosporin A since 10 times higher doses of cyclosporin A were required to obtain the same Kp values recorded for SDZ PSC 833. Moreover, the coadministration of SDZ PSC 833 increased the brain penetration of cyclosporin A, whereas the latter did not modify that of SDZ PSC 833. The increase in SDZ PSC 833 and vincristine PS values observed at high blood levels of SDZ PSC 833 are consistent with the hypothesis of a saturation of the P-glycoprotein pump present at the BBB. The involvement of P-glycoprotein in the brain passage of SDZ PSC 833 could be of great significance for clinical application of the drug in the treatment of brain cancers when it is given in combination with anticancer agents.
本研究定量评估了一种强效P-糖蛋白抑制剂SDZ PSC 833的脑渗透性及其对抗癌药物长春新碱血脑屏障（BBB）通透性（PS）的影响。在较低剂量的SDZ PSC 833时，尽管该化合物具有高亲脂性，但定义为脑血分配系数（Kp）的脑渗透性非常低。然而，在较高剂量时，SDZ PSC 833的脑渗透性显著增加。由于在研究的剂量范围内SDZ PSC 833的血药动力学证明是线性的，这些结果表明SDZ PSC 833的脑内通过具有剂量依赖性。还发现环孢素A的脑内通过也具有剂量依赖性。然而，SDZ PSC 833在BBB处抑制外排机制的效力高于环孢素A，因为需要10倍高剂量的环孢素A才能获得与SDZ PSC 833记录的相同Kp值。此外，SDZ PSC 833的共同给药增加了环孢素A的脑渗透性，而后者并未改变SDZ PSC 833的脑渗透性。在高血药水平的SDZ PSC 833下观察到的SDZ PSC 833和长春新碱PS值的增加与BBB处存在的P-糖蛋白泵饱和的假设一致。当与抗癌药物联合使用时，P-糖蛋白参与SDZ PSC 833的脑内通过对于该药物在脑癌治疗中的临床应用可能具有重要意义。
