Evaluation of a Potential Clinical Significant Drug-Drug Interaction between Digoxin and Bupropion in Cynomolgus Monkeys
Evaluation of a Potential Clinical Significant Drug-Drug Interaction between Digoxin and Bupropion in Cynomolgus Monkeys
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地高辛和安非他酮在食蟹猴中潜在临床显着药物相互作用的评估。
DOI：
10.1007/s11095-018-2525-z
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发表时间：
2019-01-01
影响因子：
3.7
通讯作者：
Hong, Kui
中科院分区：
文献类型：
--
作者：
Shen, Yang;Yu, Yang;Hong, Kui
PurposeA三期地高辛安非他酮药物相互作用的研究进行了食蟹猴，以评估安非他酮及其代谢产物对地高辛dispose.MethodsMonkeys的影响静脉输液（0.1 mg/kg）或口服剂量的地高辛（0.2 mg/kg）作为对照。在单次给药阶段，猴分别接受1.5 mg/kg安非他酮静脉输注和地高辛输注或经口给药。在多次给药期间，安非他酮口服给药q.d. 7.72 mg/kg，连续给药12天。然后分别与地高辛静脉输注或口服给药联合给药。OATP 4C 1和P-gp的肾表达examined.ResultsBupropion显着增加i. v.地高辛CLrenal 0 - 48 h的1倍，在单次给药期间。但它对地高辛的全身处置没有影响。在多次给药期间，安非他酮显着增加口服地高辛CLrenal 0 - 48 h、CLtotal 0 - 48 h、CLnon-renal 0 - 48 h的血浆暴露量，并降低其血浆暴露量。安非他酮及其代谢产物不改变肌酐清除率。OATP 4C 1位于近端小管细胞的基底外侧膜，而P-gp位于顶膜上。地高辛CL renal 0 - 48 h的增加幅度在一定程度上导致地高辛AUC降低，但肯定不是主要驱动力。单次给药后缺乏全身暴露量，但重复给药后地高辛CL非肾0 - 48 h升高介导的暴露量显著降低可能更具临床相关性。
PurposeA three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition.MethodsMonkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined.ResultsBupropion significantly increased i.v. digoxin CLrenal0-48hby 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48hand decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P-gp was on the apical membrane.ConclusionsThe effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48hcontributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48hwith repeated dosing is likely to be the more clinically relevant.