Aebi S, Schnider T W, Los G, Heath D D, Darrah D, Kirmani S, McClay E F, D'Agostino H, Plaxe S C, Fink D, De las Alas M M, Howell S B, Christen R D
Institute of Medical Oncology, University of Bern, Inselspital, Switzerland.
Cancer Chemother Pharmacol. 1999;44(3):259-65. doi: 10.1007/s002800050976.
The purpose of this study was to investigate the effect of high-dose progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics and toxicity of paclitaxel.
A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m2 administered over 3 h once every 3 weeks) until progression of disease, at which point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharmacokinetic studies of paclitaxel administered alone and with progesterone were performed in eight patients.
The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 +/- 0.94 vs. 4.15 +/- 1.63 microM; P = 0.029; mean +/- SD) and the area under the curve (AUC; 14.3 +/- 4.75 vs. 17.3 +/- 5.59 microM x h; P = 0.006) of paclitaxel. The absolute neutrophil and platelet nadir counts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive disease on paclitaxel alone had partial responses when high-dose progesterone was added to the paclitaxel regimen.
Progesterone had a statistically significant impact on the pharmacokinetics of paclitaxel. The addition of high-dose progesterone to paclitaxel is feasible, but the small number of patients prevents conclusions being drawn about the clinical efficacy of combined progesterone and paclitaxel.
本研究旨在探讨P糖蛋白抑制剂高剂量孕酮对紫杉醇药代动力学及毒性的影响。
共29例患有各种肿瘤的患者接受单药紫杉醇治疗（125mg/m²，静脉滴注3小时，每3周1次），直至疾病进展，此时20例患者（13例女性，7例男性）在紫杉醇治疗方案中加入高剂量孕酮（3g，静脉滴注24小时）。对8例患者进行了单独使用紫杉醇及联合使用孕酮时的药代动力学研究。
紫杉醇的药代动力学参数变化很大。高剂量孕酮使紫杉醇的血浆峰浓度（3.00±0.94对4.15±1.63μM；P = 0.029；均值±标准差）及曲线下面积（AUC；14.3±4.75对17.3±5.59μM·h；P = 0.006）升高。单独使用紫杉醇及联合治疗周期时，绝对中性粒细胞计数及血小板最低点计数无显著差异。20例单用紫杉醇时记录为疾病进展的患者中，3例在紫杉醇方案中加入高剂量孕酮后出现部分缓解。
孕酮对紫杉醇的药代动力学有统计学上的显著影响。在紫杉醇中加入高剂量孕酮是可行的，但患者数量较少，无法得出关于孕酮与紫杉醇联合应用临床疗效的结论。
