Jiko Mari, Yano Ikuko, Sato Eriko, Takahashi Kazushige, Motohashi Hideyuki, Masuda Satohiro, Okuda Masahiro, Ito Noriyuki, Nakamura Eijiro, Segawa Takehiko, Kamoto Toshiyuki, Ogawa Osamu, Inui Ken-Ichi
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
Int J Clin Oncol. 2007 Aug;12(4):284-90. doi: 10.1007/s10147-007-0681-y. Epub 2007 Aug 20.
We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel.
Paclitaxel was administered at 175 mg/m(2) or 150 mg/m(2) to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated.
Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-microM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel.
The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.
我们研究了紫杉醇联合卡铂或吉西他滨在泌尿生殖系统癌症患者中的药代动力学和药效学，以阐明监测紫杉醇血清浓度的意义。
分别给予10例激素难治性前列腺癌患者或6例晚期移行细胞癌患者175mg/m²或150mg/m²的紫杉醇，同时分别联合卡铂或吉西他滨。研究了药代动力学参数与血液学不良反应以及药理作用之间的关系。评估了包括多药耐药蛋白1（ABCB1）、细胞色素P450 2C8（CYP2C8）、细胞色素P450 3A4（CYP3A4）和细胞色素P450 3A5（CYP3A5）单核苷酸多态性在内的患者特征对紫杉醇总体清除率的影响。
卡铂或吉西他滨治疗的患者在静脉输注紫杉醇后的总体清除率和稳态分布容积无显著差异。吉西他滨方案导致中性粒细胞和血小板减少的百分比显著高于卡铂方案，并且与输注结束时观察到的浓度或紫杉醇浓度高于0.1μM的时间呈显著正相关。前列腺癌患者治疗后前列腺特异性抗原的降低与紫杉醇暴露程度无正相关。多药耐药蛋白1外显子26（C3435T）和外显子21（G2677A/T）的多态性以及细胞色素P450 3A5*1等位基因均未显著影响紫杉醇的总体清除率。
吉西他滨会增强紫杉醇的血液学副作用，且与紫杉醇药代动力学相关。监测紫杉醇血清浓度将有助于治疗，减少骨髓抑制且不损失任何治疗效果。
