Taxol metabolism and disposition in cancer patients.
Taxol metabolism and disposition in cancer patients.
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发表时间：
1995-04
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通讯作者：
Thomas Walle;U. Walle;G. Kumar;K. Bhalla
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作者：
Thomas Walle;U. Walle;G. Kumar;K. Bhalla
本研究的目的是确定紫杉醇在癌症患者体内的代谢命运和处置。5例患者接受225或250 mg/m2的紫杉醇与100 microCi的[3 H]紫杉醇作为3小时输注，随后顺铂和5-氟尿嘧啶。收集120小时的尿液、粪便和血液样本，并通过反相HPLC和串联MS分析总放射性、紫杉醇和代谢产物。总尿液排泄量为剂量的14.3 +/- 1.4%（SE），主要排泄产物为原型紫杉醇和未知极性代谢产物。总粪便排泄量为71.1 +/-8.2%，6 α-羟基紫杉醇是迄今为止最大的组分。从粪便提取物中也可以鉴定出未改变的紫杉醇和其他四种代谢产物。未改变的紫杉醇的血浆曲线下面积为20.5 +/- 2.3 microM.hr，总紫杉醇代谢物的曲线下面积为14.2 +/- 4.5 μ M. hr。然而，总代谢物的半衰期（5.6 +/- 0.4 hr）大大超过未改变的紫杉醇（2.9 +/- 0.3 hr）。因此，在紫杉醇输注后5小时，五种代谢物的血浆浓度一起超过紫杉醇浓度的2.4倍。这项研究的结果应该是重要的指导，以进一步治疗评价这种药物。
The objective of this study was to determine the metabolic fate and disposition of taxol in cancer patients. Five patients received 225 or 250 mg/m2 of taxol together with 100 microCi of [3H]taxol as a 3-hr infusion, followed by cisplatin and 5-fluorouracil. Urine, feces, and blood samples were collected for 120 hr and analyzed for total radioactivity, taxol, and metabolites by reversed-phase HPLC and tandem MS. Total urinary excretion was 14.3 +/- 1.4% (SE) of the dose, with unchanged taxol and an unknown polar metabolite as the main excretion products. Total fecal excretion was 71.1 +/- 8.2%, with 6 alpha-hydroxytaxol being the largest component by far. Unchanged taxol and four other metabolites could also be identified from fecal extracts. The plasma area under the curve for unchanged taxol was 20.5 +/- 2.3 microM.hr and that for total taxol metabolites was 14.2 +/- 4.5 microM.hr. The half-life of total metabolites (5.6 +/- 0.4 hr), however, greatly exceeded that of unchanged taxol (2.9 +/- 0.3 hr). Thus, at 5-hr posttaxol infusion, the plasma concentrations of the five metabolites together exceeded the taxol concentration by 2.4-fold. The findings from this study should be of importance as a guide to further therapeutic evaluation of this drug.