Modification of CCNU pharmacokinetics by misonidazole--a major mechanism of chemosensitization in mice.
Modification of CCNU pharmacokinetics by misonidazole--a major mechanism of chemosensitization in mice.
复制标题
米索硝唑对 CCNU 药代动力学的改变——小鼠化疗增敏的主要机制。
DOI：
10.1038/bjc.1983.104
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发表时间：
1983-05
影响因子：
8.8
通讯作者：
Workman, P
中科院分区：
文献类型：
--
作者：
Lee, F Y;Workman, P
研究了米索硝唑（MISO）对1-（2-氯乙基）-3-环己基-1-亚硝基脲（CCNU）在小鼠体内药动学的影响。采用高效液相色谱法测定CCNU及其单羟基化代谢物。在没有MISO的情况下，CCNU的血浆消失是双相的，t1 /2 α为2.3 min， t1 /2 β为53 min。CCNU的单羟基化代谢物也遵循双相清除动力学。在CCNU前30分钟给予大剂量单次MISO (0.5 mg g-1)，将t1 /2 α延长了2.6倍，但对t1 /2 β没有影响。此外，表观分布体积减少了1.6倍。因此，CCNU的血浆曲线下面积（AUC0 -∞）增加了1.7倍，总亚硝基脲（CCNU +单羟基化代谢物）增加了2.0倍。MISO对CCNU动力学的影响取决于MISO的剂量和血浆浓度，以及MISO和CCNU给药的间隔时间。在KHT、RIF-1和EMT6小鼠肿瘤和HT29异种移植瘤中测定CCNU的浓度。对于所有4个肿瘤，0.5 mg g-1 MISO使CCNU和总亚硝基脲的肿瘤浓度显著升高（2-2.5倍）。在KHT肿瘤中更详细的研究表明，在达到肿瘤CCNU浓度峰值之前存在明显的滞后期，MISO使峰值浓度增加了约2.4倍。相比之下，血浆中没有这种滞后期，MISO也没有增加血浆中CCNU的峰值浓度。这些数据有力地表明，体内大剂量MISO的药代动力学改变可能是CCNU细胞毒性增强的一个主要因素。
We have investigated the effect of misonidazole (MISO) on the pharmacokinetics of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in mice. CCNU and its monohydroxylated metabolites were measured using a high performance liquid chromatography (HPLC) method. In the absence of MISO the plasma disappearance of CCNU was biphasic with a t 1/2 alpha of 2.3 min and a t 1/2 beta of 53 min. The monohydroxylated metabolites of CCNU also followed biphasic clearance kinetics. A large single dose of MISO (0.5 mg g-1), given i.p. 30 min prior to CCNU, prolonged the t 1/2 alpha by a factor of 2.6 but had no effect on t 1/2 beta. In addition, the apparent volume of distribution was decreased by a factor of 1.6. Consequently, the plasma area under the curve (AUC0 - infinity) was increased by a factor of 1.7 for CCNU and by a factor of 2.0 for total nitrosourea (CCNU + monohydroxylated metabolites). The effects of MISO on CCNU kinetics were dependent on MISO dose and plasma concentration and on the interval between MISO and CCNU administration. The concentration of CCNU was measured in 4 tumours: the KHT, RIF-1 and EMT6 mouse tumours, and the HT29 xenograft. For all 4 tumours, 0.5 mg g-1 MISO raised the tumour concentrations of CCNU and total nitrosourea by a considerable amount (2-2.5 times). More detailed studies in the KHT tumour demonstrated that there was a significant lag period before peak tumour CCNU concentrations were reached, and that MISO increased the peak concentrations by a factor of about 2.4. In contrast, there was no such lag period for the plasma and MISO did not increase the plasma peak CCNU concentrations. These data strongly suggest that modification of the pharmacokinetics may be a major contributory factor in the enhancement of CCNU cytotoxicity by large single doses of MISO in vivo.