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

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（Tmax）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Tmax，而合用酮康唑后，咪达唑仑灌胃给药的Tmax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。%OBJECTIVE To investigate the effect of ketoconazole on the pharmacokinetic (PK) behaviors of midazolam and its metabolite through intranasal and intragastric(ig) routes in rats. METHODS Twenty-four rats were evenly divided into 4 groups. Two groups of rats were administrated singly with midazolam (1 mg∙kg-1) through intranasal or ig route. The other two groups were concomitant with CYP3A inhibitor,ketoconazole(30 mg∙kg-1),midazolam(1 mg∙kg-1)through the same two routes. Blood samples were collected from different time points. Plasma concentration of midazolam and 1′-hydroxymidazolam was determined. Major pharmacokinetic parameters were calculated and statistical tests were performed by using t test. RESULTS Tmax was about 2 and 25 min for rats administered singly with midazolam via intranasal or ig routes,respectively and AUC was 296 and 179 μg∙L-1∙h, respectively. When concomitant with ketoconazole,AUC increased to 2.1 and 3.3 folds the original value for intranasal and ig routes,respectively. However,the Tmax value of midazolam via intranasally didn′t change after being coadministrated with ketoconazole,but Tmax increased to 1.14 h via ig. CONCLUSION Compared with administration via ig,intranasal route administrated midazolam displays significant advantages of faster absorption and higher exposure,which are vital for the first aid. Concomitant with CYP3A inhibitor and midazolam via intranasal route,the absorption speed is not affected,but with the metabolism blocked,the systemic exposure is greatly elevated. While via ig,both absorption speed and metabolism are inhibited. The dose should be cut down or the dosing interval increased in clinic practice in this concomitant situation.