Grimison Peter, Galettis Peter, Manners Susan, Jelinek Maria, Metharom Ekkaphon, de Souza Paul L, Liauw Winston, Links Matthew J
Cancer Pharmacology Therapeutics Group, St George Hospital, Sydney, Australia.
J Clin Oncol. 2007 Dec 20;25(36):5704-9. doi: 10.1200/JCO.2007.10.7078.
Controversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design.
We randomly assigned 33 patients to a standard dose of 1,000 mg/m2 over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood samples were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes.
Intracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels.
This work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within individuals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.
关于吉西他滨给药的最佳剂量率存在争议。从药理学角度来看，延长输注时间可增加细胞内蓄积，但在一项大型随机研究中这并未转化为显著益处。本研究的目的是采用交叉设计比较给予30分钟或100分钟的吉西他滨的细胞内药代动力学。
我们将33例患者随机分为两组，分别接受1000mg/m²的标准剂量，输注时间为30分钟或100分钟。在第二周，他们转换为交替方案。在吉西他滨输注后的不同时间采集血样。采用高效液相色谱法（HPLC）测定血浆中的吉西他滨和二氟脱氧尿苷，并采用HPLC测定白细胞中的三磷酸吉西他滨。
在100分钟输注期间细胞内蓄积更多，这与先前的数据一致。这种效应因第1周和第2周之间三磷酸吉西他滨蓄积增加而受到混淆，这与吉西他滨蓄积的自我诱导一致。存在显著的异质性：27%的患者在30分钟输注期间白细胞蓄积更多（无论治疗顺序如何）。白细胞中三磷酸吉西他滨水平相对较高的患者往往给药不足较少，且周期中期中性粒细胞减少更多。然而，这一观察结果与血浆吉西他滨水平无关。
这项研究发现个体之间和个体内部三磷酸吉西他滨细胞内蓄积存在显著差异，并提供证据表明这种差异具有潜在的临床意义。观察到的吉西他滨代谢的自我诱导对核苷类似物的给药具有广泛影响。
