P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 mu g/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 +/- 39.37 mmHg min versus 4607 +/- 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0-40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells.
机构:
Massachusetts Gen Hosp, Heart Failure & Transplantat Unit, Boston, MA 02114 USAMassachusetts Gen Hosp, Heart Failure & Transplantat Unit, Boston, MA 02114 USA
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Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, EnglandPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Fenner, K. S.
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Troutman, M. D.
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Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Groton, CT USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Troutman, M. D.
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Kempshall, S.
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Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, EnglandPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Kempshall, S.
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Cook, J. A.
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Pfizer Global Res & Dev, Dept Clin Pharmacol, Groton, CT USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Cook, J. A.
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Ware, J. A.
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Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Ann Arbor, MI USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Ware, J. A.
;
Smith, D. A.
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Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, EnglandPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Smith, D. A.
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Lee, C. A.
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机构:
Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
机构:
Massachusetts Gen Hosp, Heart Failure & Transplantat Unit, Boston, MA 02114 USAMassachusetts Gen Hosp, Heart Failure & Transplantat Unit, Boston, MA 02114 USA
机构:
Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, EnglandPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Fenner, K. S.
;
Troutman, M. D.
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h-index: 0
机构:
Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Groton, CT USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Troutman, M. D.
;
Kempshall, S.
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h-index: 0
机构:
Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, EnglandPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Kempshall, S.
;
Cook, J. A.
论文数: 0引用数: 0
h-index: 0
机构:
Pfizer Global Res & Dev, Dept Clin Pharmacol, Groton, CT USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Cook, J. A.
;
Ware, J. A.
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h-index: 0
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Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Ann Arbor, MI USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Ware, J. A.
;
Smith, D. A.
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h-index: 0
机构:
Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, EnglandPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA
Smith, D. A.
;
Lee, C. A.
论文数: 0引用数: 0
h-index: 0
机构:
Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USAPfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA USA