Yang Shen1,2, Yang Yu3,4, Wei Lai5, Shuai Li5, Zixuan Xu5, Jiejing Jin1, Xia Yan1, Han Xing6, Xijing Chen6, Aizhen Xiong3, Chunhua Xia7, Jiake He8,9, Kui Hong1,2,5. 1. Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi,, China. 2. The Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China. 3. Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, 330006, Jiangxi,, China. 4. Clinical Pharmacology Institute, Department of Pharmacy, Nanchang University, Bayi Avenue No. 461, Nanchang, 330006, Jiangxi,, China. 5. Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, 330006, Jiangxi, China. 6. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. 7. Clinical Pharmacology Institute, Department of Pharmacy, Nanchang University, Bayi Avenue No. 461, Nanchang, 330006, Jiangxi,, China. xch720917@163.com. 8. Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, 330006, Jiangxi,, China. hjk987@sina.com. 9. Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, 330006, Jiangxi, China. hjk987@sina.com.
Abstract
PURPOSE: A 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. METHODS: Monkeys 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. RESULTS: Bupropion significantly increased i.v. digoxin CLrenal0-48h by 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-renal0-48h and 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. CONCLUSIONS: The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed 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-renal0-48h with repeated dosing is likely to be the more clinically relevant.
PURPOSE: A 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. METHODS: Monkeys 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. RESULTS:Bupropion significantly increased i.v. digoxin CLrenal0-48h by 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-renal0-48h and 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. CONCLUSIONS: The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed 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-renal0-48h with repeated dosing is likely to be the more clinically relevant.
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