酮康唑对大鼠鼻腔和灌胃给予咪达唑仑及其代谢产物药动学差异的影响

发布时间：2018-12-21 07:16

【摘要】：目的在系统比较大鼠鼻腔和灌胃给予咪达唑仑药动学特征的基础上,进一步比较酮康唑对2种给药途径药动学的影响。方法 24只大鼠随机分为4组,每组6只。其中2组分别经鼻腔或灌胃只给予咪达唑仑(1 mg?kg~(- 1)),另外2组联用细胞色素P450酶3A(CYP3A)抑制剂酮康唑(30 mg?kg~(- 1))后再分别经鼻腔或灌胃给予咪达唑仑,不同时间点采集血样,测定咪达唑仑和1′-羟基咪达唑仑浓度,计算药代动力学参数,并进行统计学分析。结果大鼠单独经鼻腔和灌胃给予咪达唑仑后,原型药物的达峰时间(T_(max))分别约为2和25 min,药时曲线下面积(AUC)分别为296和179μg?L~(-1)?h。合用酮康唑后,在鼻腔和灌胃给药条件下,咪达唑仑原型药物在大鼠体内的AUC分别增加到原来的2.1和3.3倍。但是,酮康唑不改变咪达唑仑鼻腔给药的T_(max),而合用酮康唑后,咪达唑仑灌胃给药的T_(max)延长至1.14h。结论咪达唑仑经鼻腔给药与经口服给药相比,吸收迅速、药物暴露量大,更适合于临床急救。咪达唑仑经鼻腔给药合用酮康唑后,不改变吸收速度,但抑制其代谢转化,药物体内驻留时间明显延长;咪达唑仑口服给药合并给予酮康唑后,吸收减慢,抑制代谢转化,体内药物暴露量明显增加。由于咪达唑仑的中枢镇静作用,2种途径合用酮康唑时均应考虑适当减少给药剂量或延长给药间隔。
[Abstract]:Objective to compare the effects of ketoconazole on the pharmacokinetics of midazolam in nasal cavity and intragastric administration of rats. Methods 24 rats were randomly divided into 4 groups with 6 rats in each group. Two groups were given midazolam (1 mg?kg~ (-1),) through nasal cavity or intragastric perfusion. The other two groups were treated with ketoconazole (30 mg?kg~ (-1), a cytochrome P450 enzyme 3A (CYP3A) inhibitor, and then given midazolam through nasal cavity or intragastric administration respectively. Blood samples were collected at different time points. The concentrations of midazolam and 1-hydroxy-midazolam were measured and the pharmacokinetic parameters were calculated and analyzed statistically. Results after midazolam was given to rats alone through nasal cavity and intragastric administration, the peak time (T _ (max) of the original drug was about 2 and 25 min, respectively. The (AUC) under the curve was 296,179 渭 g / L ~ (-1)? h, respectively. After combined with ketoconazole, the AUC of midazolam in rats was increased by 2.1 and 3.3 times, respectively, in nasal cavity and intragastric administration. However, ketoconazole did not change the T _ (max), of midazolam nasal administration, but after combined with ketoconazole, the T _ (max) of midazolam was prolonged to 1.14 h. Conclusion midazolam by nasal administration is more suitable for clinical first aid because of its rapid absorption and high drug exposure. After nasal administration of midazolam combined with ketoconazole, the absorption rate was not changed, but the metabolic transformation of midazolam was inhibited. After oral administration of midazolam combined with ketoconazole, absorption slowed down, metabolic transformation was inhibited, and drug exposure in vivo increased significantly. Due to the central sedative effect of midazolam, we should consider reducing the dosage or prolonging the interval of administration when combined with ketoconazole.
【作者单位】：抗毒药物与毒理学国家重点实验室军事医学科学院毒物药物研究所;
【基金】：国家科技重大专项(2012ZX09301003-001-009);国家科技重大专项(2013ZX09J13103-01B);国家科技重大专项(2014ZX09507001003);国家科技重大专项(2014ZX09J14103-01A)~~
【分类号】：R965

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