Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.
Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.
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新候选药物 CuGTSM 在门克斯病小鼠模型中的药代动力学。
DOI：
10.1007/s11095-021-03090-0
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Ito K.
中科院分区：
文献类型：
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作者：
Yamagishi Y;Kudo T;Oyumi M;Sakamoto Y;Takahashi K;Akashi T;Kobayashi S;Kawakami T;Goda H;Sato Y;Mimaki M;Kodama H;Munakata M;Makino K;Takahashi H;Fukami T;Ito K.
目的门克斯病是一种罕见的遗传性疾病，由于ATP 7A基因突变引起的全身性铜缺乏导致严重的神经退行性疾病。目前的肠胃外药物具有有限的功效，因此需要可以口服施用的有效药物。本研究集中于甘氨酰-双（N（4）-甲基氨基硫脲）-铜（II）（CuGTSM），其已在黄斑小鼠（Menkes病的小鼠模型）中显示出疗效，并检查了其药代动力学。方法将CuGTSM或nCuGTSM（10 mg/kg）经口给予雄性黄斑小鼠或C3 H/HeNCrl小鼠（对照组），连续采血，测定血浆中CuGTSM的浓度。采用LC-MS/MS法测定CuGTSM和GTSM的血药浓度，计算药代动力学参数。当给予nCuGTSM时，两种小鼠品系的CuGTSM和GTSM的Cmax均明显高于给予CuGTSM时，并且平均停留时间均长于CuGTSM。与黄斑小鼠，AUC比（GTSM/CuGTSM）显着较高，血浆CuGTSM浓度低于C3 H/HeNCrl小鼠时，无论是CuGTSM或nCuGTSM gived.ConclusionAbsorption口服给药CuGTSM证实在黄斑小鼠，和纳米制剂提高了吸收和保留的CuGTSM在体内。然而，在黄斑小鼠中的CuGTSM的血浆浓度低于对照小鼠，表明CuGTSM更容易解离。
PurposeMenkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of theATP7Agene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated.MethodsCuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated.ResultsWhen CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmaxwas markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered.ConclusionAbsorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.