The effect of systemic hyperthermia on melphalan pharmacokinetics in mice.
The effect of systemic hyperthermia on melphalan pharmacokinetics in mice.
复制标题
全身性高温对小鼠Melphalan药代动力学的影响。
DOI：
10.1038/bjc.1985.11
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发表时间：
1985-01
影响因子：
8.8
通讯作者：
Bleehen, N M
中科院分区：
文献类型：
--
作者：
Honess, D J;Donaldson, J;Workman, P;Bleehen, N M
在C3 H小鼠中研究了在41 ℃下全身加热45分钟对腹膜内施用的美法仑（MEL）的血浆和RIF-1肿瘤药代动力学的影响。该热剂量在肿瘤中比在骨髓细胞中引起更大的MEL增强，导致联合治疗的治疗增益（Honess & Bleehen，1985）。在加热开始时给予MEL（7.5 mg kg-1），并通过高效液相色谱法（HPLC）测定20-90 min的浓度。有或没有热峰浓度达到20分钟，并在血浆中3至4微克ml-1和1-3微克g-1的肿瘤。在注射后20分钟，在加热的动物中发现血浆和肿瘤中的MEL浓度较高，但血浆中的效应（2.5-4倍）大于肿瘤中的效应（1.5-2倍），其中差异并不总是显著的。在7.5 mg kg-1剂量给药后40分钟，加热动物的血浆和肿瘤浓度分别相当于12.5 mg kg-1和8.5 mg kg-1（未加热）给药后的浓度。加热动物的肿瘤/血浆比通常低于未加热动物，后者通常超过100%。未加热动物的表观血浆消除半衰期（t1/2）为17.5-25 min，加热动物为24-44 min。加热动物的曲线下面积（AUC）增加了1.2-1.5倍，至少部分是由于分布容积降低。热诱导的MEL暴露增加可能与对药物的反应增强有关，但似乎不能解释与单独MEL相比的治疗增益。
The effect of 45 min systemic heating at 41 degrees C on plasma and RIF-1 tumour pharmacokinetics of intraperitoneally administered melphalan (MEL) was studied in C3H mice. This heat dose causes greater potentiation of MEL in tumour than in marrow cells, resulting in a therapeutic gain for the combined therapy (Honess & Bleehen, 1985). MEL (7.5 mg kg-1) was administered at the start of heating and concentrations assayed from 20-90 min by high-performance liquid chromatography (HPLC). With or without heat peak concentrations were achieved by 20 min and were 3 to 4 micrograms ml-1 in plasma and 1-3 micrograms g-1 in tumour. Higher MEL concentrations in both plasma and tumour were found in heated animals at times after 20 min from injection, but the effect was greater in plasma (2.5-4 fold) than in tumour (1.5-2 fold) where differences were not always significant. At 40 min after a dose of 7.5 mg kg-1, plasma and tumour concentrations in heated animals were equivalent to those after 12.5 mg kg-1 and 8.5 mg kg-1, respectively, without heating. Tumour/plasma ratios were usually lower in heated than in unheated animals where they often exceeded 100%. The apparent plasma elimination half-life (t1/2) was 17.5-25 min in unheated and 24-44 min in heated animals. The area under the curve (AUC) was increased by a factor of 1.2-1.5 in heated animals, at least partly due to a decrease in volume of distribution. The heat induced increase in MEL exposure may be involved in the enhanced response to the drug, but does not appear to explain the therapeutic gain compaired to MEL alone.