Lush R M, Meadows B, Fojo A T, Kalafsky G, Smith H T, Bates S, Figg W D
Branch of Clinical Pharmacology, National Cancer Institute, Bethesda, Maryland 20892, USA.
J Clin Pharmacol. 1997 Feb;37(2):123-8. doi: 10.1002/j.1552-4604.1997.tb04770.x.
Resistant cancer cells have been shown to overexpress a 170-kd membrane glycoprotein called P-glycoprotein. P-glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy-dependent efflux pump that decreases intracellular drug concentrations. A variety of nonchemotherapeutic agents have been shown to inhibit P-glycoprotein-dependent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppressive derivative of cyclosporin D with the ability to reverse multidrug resistance because of P-glycoprotein overexpression in vitro. As part of early clinical development of PSC 833, the authors investigated the bioavailability of an oral formulation of PSC 833. PSC 833 (3 mg/kg) was administered as a 2-hour intravenous infusion on day 1 of the treatment cycle. Serial blood samples for the determination of PSC 833 whole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral dose (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intravenous data were best described by a two-compartment open model. The oral data also were described using a two-compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra- and interpatient variability in the pharmacokinetics of PSC 833 in these patients. The absolute bioavailability of PSC 833 was 34% but ranged from 3% to 58% of the administered dose. The clearance (CI) of PSC 833, in general, was consistent between the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.
已证实耐药癌细胞会过度表达一种名为P - 糖蛋白的170-kd膜糖蛋白。P - 糖蛋白是多药耐药1基因的产物，作为一种能量依赖性外排泵发挥作用，可降低细胞内药物浓度。多种非化疗药物已被证明可抑制P - 糖蛋白依赖性药物外排，包括环孢素。PSC 833是环孢素D的一种非免疫抑制衍生物，由于其在体外可逆转因P - 糖蛋白过度表达导致的多药耐药性。作为PSC 833早期临床开发的一部分，作者研究了PSC 833口服制剂的生物利用度。在治疗周期的第1天，以2小时静脉输注的方式给予PSC 833（3 mg/kg）。在静脉给药和口服给药后均采集系列血样以测定PSC 833全血浓度。在研究的第5天，患者接受单次口服剂量（9 mg/kg）的PSC 833。共治疗了14名患者。静脉给药数据用二室开放模型能得到最佳描述。口服给药数据也用二室模型描述，口服吸收纳入了滞后时间以考虑可能的吸收延迟。这些患者中PSC 833的药代动力学存在较大的患者内和患者间变异性。PSC 833的绝对生物利用度为34%，但占给药剂量的比例范围为3%至58%。一般来说，两种给药剂型的PSC 833清除率（CI）是一致的。PSC 833的药代动力学行为似乎与环孢素相似。
