Loos W J, Gelderblom H J, Verweij J, Brouwer E, de Jonge M J, Sparreboom A
Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
Anticancer Drugs. 2000 Oct;11(9):673-80. doi: 10.1097/00001813-200010000-00001.
Gender-dependent differences in the clinical pharmacokinetic behavior of various drugs have been documented previously. Most commonly, these differences are associated with differences in body composition, renal elimination, drug absorption or hepatic metabolism. Gender-dependent differences in the pharmacokinetics of topotecan (Hycamtin) have not yet been described. In this report, pharmacokinetic data of the lactone and carboxylate forms of topotecan were derived from clinical studies in which topotecan was administered either orally or i.v. to a total of 55 males and 37 females. A significant difference (p=0.0082) of 38% was found between the apparent clearance of topotecan lactone after oral administration in males (237+/-105 l/h) and females (163+/-62.5 l/h). When adjusted for body surface area, this difference remained significant (p=0.031). Similarly, differences were noted in the percentage of topotecan in the lactone form (37.1+/-5.32 versus 41.7+/-6.51%, p=0.0076). Statistical analysis revealed that individual hematocrit values, which were consistently lower in females (p<0.023), were a significant predictor of the apparent topotecan lactone clearance. This was confirmed experimentally in in vitro incubation studies in whole blood using artificially altered hematocrit values and in blood samples from both male and female volunteers. Topotecan is thus subject to significant gender-dependent differences in pharmacokinetics that arise as a result of a physiological difference in hematocrit values between males and females. This finding may have significant implications for the interpretation of the relationships between pharmacokinetics and pharmacodynamic outcome of topotecan treatment, and may provide a basis for the development and refinement of future clinical protocols.
此前已有文献记载了各种药物临床药代动力学行为的性别差异。最常见的是，这些差异与身体组成、肾脏排泄、药物吸收或肝脏代谢的差异有关。拓扑替康（希罗达）药代动力学的性别差异尚未见报道。在本报告中，拓扑替康内酯和羧酸盐形式的药代动力学数据来自临床研究，其中拓扑替康通过口服或静脉注射给药于总共55名男性和37名女性。男性口服拓扑替康内酯后的表观清除率（237±105 l/h）与女性（163±62.5 l/h）之间存在38%的显著差异（p = 0.0082）。按体表面积校正后，这种差异仍然显著（p = 0.031）。同样，内酯形式的拓扑替康百分比也存在差异（37.1±5.32%对41.7±6.51%，p = 0.0076）。统计分析表明，女性个体的血细胞比容值始终较低（p<0.023），是拓扑替康内酯表观清除率的重要预测指标。在使用人工改变血细胞比容值的全血体外孵育研究以及来自男性和女性志愿者的血样中，这一点得到了实验证实。因此，拓扑替康在药代动力学上存在显著的性别差异，这是由于男性和女性血细胞比容值的生理差异所致。这一发现可能对拓扑替康治疗的药代动力学与药效学结果之间关系的解释具有重要意义，并可能为未来临床方案的制定和完善提供依据。
