Decreased sensitivity to metocurine during long-term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes.
Decreased sensitivity to metocurine during long-term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes.
复制标题
长期苯妥英治疗期间对美托库林的敏感性降低可能归因于蛋白质结合和乙酰胆碱受体的变化。
DOI：
10.1097/00000542-199209000-00015
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发表时间：
1992
期刊：
影响因子：
8.8
通讯作者：
Martyn,JA
中科院分区：
文献类型：
--
作者：
Kim,CS;Arnold,FJ;Itani,MS;Martyn,JA
长期苯妥英钠治疗可诱导对甲氧箭毒神经肌肉阻滞作用的抵抗。在大鼠中检测了这归因于与α 1-酸性糖蛋白（AAG）浓度增加相关的药物血浆蛋白结合增加（游离分数降低）或归因于肌膜乙酰胆碱受体（AChR）增殖的假设。苯妥英40 mg. kg ~（-1），每日2次腹腔注射（n= 12），评价其神经肌肉药效学，并与时间匹配的对照组（n= 10）进行比较。通过平衡透析测定蛋白结合，通过放射免疫扩散测定AAG浓度，通过125 I-α-银环蛇毒素结合测定AChR。苯妥英组基线抽搐高度50%抑制的有效剂量（ED 50）显著高于对照组（15.03+/-1.65微克）。kg-1与9.98+/-0.69微克。kg ~（-1）。AAG的浓度从133.8+/-7.8微克逐渐增加。ml-1，至343.1+/-58.0微克。ml-1，至1，729.5 +/-422.3微克。ml-1。血浆中AAG浓度的诱导依赖于血浆苯妥英浓度，在苯妥英14天后最为显著（r= 0.77; P <0.01; n= 22）。与对照组相比，苯妥英组的甲香豆素游离分数显著降低（67.2+/-0.18% vs. 74.5+/-2.5%）。AAG浓度升高与游离分数降低呈显著负相关（r= 0.65）。（250字处删节）
Long-term phenytoin therapy induces resistance to the neuromuscular blocking effects of metocurine. The hypothesis that this is attributable to increased plasma protein binding of the drug (decreased free fraction) related to increased concentrations of alpha 1-acid glycoprotein (AAG) or attributable to the proliferation of acetylcholine receptors (AChR) at the muscle membrane was tested in the rat. After 14 days of phenytoin 40 mg. kg-1, administered intraperitoneally twice daily (n= 12), the neuromuscular pharmacodynamics were evaluated and compared with those of time-matched controls (n= 10). Protein binding was measured by equilibrium dialysis, AAG concentrations by radial immunodiffusion assay, and AChR by 125I-alpha-bungarotoxin binding. The effective dose for 50% inhibition of baseline twitch height (ED50) was significantly greater in the phenytoin group than in the control group (15.03+/-1.65 micrograms. kg-1 vs. 9.98+/-0.69 micrograms. kg-1, respectively). The concentrations of AAG increased gradually from 133.8+/-7.8 micrograms. ml-1 at day 0, to 343.1+/-58.0 micrograms. ml-1 at day 7, to 1,729.5+/-422.3 micrograms. ml-1 at day 14 in the phenytoin group. The induction of AAG concentrations in plasma was dependent on plasma phenytoin concentrations and was most prominent after 14 days of phenytoin (r= 0.77; P less than 0.01; n= 22). The free fraction of metocurine was significantly decreased in the phenytoin group compared to the control group (67.2+/-0.18% vs. 74.5+/-2.5%). There was a significant negative correlation between increased AAG concentrations and decreased free fraction (r= 0.65).(ABSTRACT TRUNCATED AT 250 WORDS)