Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers
Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers
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DOI：
10.1007/s10147-007-0681-y
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发表时间：
2007-08-01
影响因子：
3.3
通讯作者：
Inui, Ken-Ichi
中科院分区：
文献类型：
--
作者：
Jiko, Mari;Yano, Ikuko;Inui, Ken-Ichi
研究背景：我们研究了紫杉醇联合卡铂或吉西他滨治疗泌尿生殖系统肿瘤患者的药代动力学和药效学，以阐明紫杉醇血药浓度监测的意义。紫杉醇以175 mg/m2或150 mg/m2的剂量分别与卡铂或吉西他滨一起沿着给药于难治性前列腺癌（n = 10）或晚期移行细胞癌（n = 6）患者。研究了药代动力学参数与血液学不良反应以及药理学作用之间的关系。评估患者特征，包括MDR 1（ABCB 1）、CYP 2C 8、CYP 3A 4和CYP 3A 5的单核苷酸多态性对紫杉醇总体清除率的影响。静脉输注紫杉醇后，卡铂或吉西他滨患者的稳态总清除率和分布容积无显著差异。吉西他滨方案的中性粒细胞和血小板减少百分比显著大于卡铂方案，并且与输注结束时观察到的浓度或紫杉醇浓度高于0.1 μ M的时间呈显著正相关。治疗后前列腺特异性抗原的降低与前列腺癌患者中紫杉醇暴露的程度不呈正相关。MDR 1基因第26外显子（C3435 T）和第21外显子（G2677 A/T）多态性及CYP 3A 5 *1等位基因均不影响紫杉醇的总体清除率。吉西他滨可加重紫杉醇的血液学副作用，且与紫杉醇的药代动力学相关。监测紫杉醇的血清浓度将有助于治疗，具有较少的骨髓抑制并且没有任何治疗功效损失。
Background 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.Methods. Paclitaxel was administered at 175mg/m(2) or 150mg/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.Results. 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-mu M 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.Conclusion. 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.