Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication
Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication
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脂肪乳输注对急性过量大鼠模型帕潘立酮药代动力学的影响：帕潘立酮中毒的潜在紧急治疗方法
DOI：
10.1016/j.ejps.2017.08.010
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发表时间：
2017
影响因子：
4.6
通讯作者：
Okuda Masahiro
中科院分区：
文献类型：
--
作者：
Enokiya Tomoyuki;Zhang Erquan;Ikemura Kenji;Muraki Yuichi;Iwashita Yoshiaki;Iwamoto Takuya;Imai Hiroshi;Maruyama Kazuo;Okuda Masahiro
帕利哌酮以浓度依赖性方式抑制心脏复极。同时，静脉注射脂肪乳剂（ILE）已被确立为亲脂性药物的解毒疗法。然而，ILE给药后各种药物的药代动力学变化仍有待澄清。我们的目的是阐明持续输注ILE对大鼠中过量帕利哌酮药代动力学的影响。自由活动的雄性Wistar大鼠经口给予帕利哌酮（20 mg/kg）。在帕利哌酮给药后30 min开始连续输注（初始负荷剂量：4 ml/kg，持续10 min，随后4 ml/kg/h，持续12 h）ILE或醋酸林格氏溶液（AR）。给药后12 h监测帕利哌酮的血药浓度曲线。比较ILE组和AR组之间帕利哌酮的血浆浓度和组织/血浆浓度比。输注ILE的大鼠组显示出较高的浓度-时间曲线下面积（平均值[S.D.]：与AR组相比，6102 [900.9]vs.3407 [992.1] ng h ml-1，p= 0.02）和更长的消除半衰期（t1/2）（4.1 [0.9]vs.2.2 [0.4] h，p= 0.02）。ILE大鼠中帕利哌酮的组织/血浆浓度比低于AR大鼠（心脏中为1.98 [0.70]vs.3.82 [1.47]，p= 0.04;脑中为0.28 [0.29]vs.1.27 [0.58]，p< 0.001）。结论：持续输注ILE可减少帕利哌酮在大鼠体内的组织分布，延长帕利哌酮的t1/2。这些结果表明，持续输注ILE可作为急性帕潘立酮中毒的紧急治疗。
Paliperidone prolongs cardiac repolarization in a concentration-dependent manner. Meanwhile, continuous infusion of intravenous lipid emulsion (ILE) has been established as a detoxification therapy for lipophilic drugs. However, this change in pharmacokinetics of various drugs following ILE administration remains to be clarified. Our objective is to clarify the effect of continuous infusion of ILE on the pharmacokinetics of overdosed paliperidone in rats. Paliperidone (20 mg/kg) was administered orally to free-moving male Wistar rats. Continuous infusion (initial loading dose: 4 ml/kg for 10 min, followed by 4 ml/kg/h for 12 h) of ILE or acetated Ringer's solution (AR) was initiated 30 min after paliperidone administration. Plasma concentration profile of paliperidone was monitored for 12 h after administration. The plasma concentration and tissue/plasma concentration ratios of paliperidone were compared between ILE and AR groups. The rat group infused with ILE showed a higher area under the concentration–time curve (mean [S.D.]: 6102 [900.9]vs.3407 [992.1] ng h ml− 1,p= 0.02) and longer elimination half-time (t1/2) (4.1 [0.9]vs.2.2 [0.4] h,p= 0.02) compared with the AR group. Tissue/plasma concentration ratios of paliperidone were lower in ILE rats than in AR rats (1.98 [0.70]vs.3.82 [1.47] in the heart,p= 0.04; 0.28 [0.29]vs.1.27 [0.58] in the brain,p< 0.001). In conclusion, continuous infusion of ILE would reduce tissue distribution and prolonged the t1/2of paliperidone in rats. These results suggest that continuous infusion of ILE has potential as an emergency treatment for acute paliperidone intoxication.