Modeling Cardiac Uptake and Negative Inotropic Response of Verapamil in Rat Heart: Effect of Amiodarone
- 130 Downloads
To determine the effect of the P-glycoprotein (Pgp) modulator amiodarone on the pharmacokinetics and pharmacodynamics (PK/PD) of Pgp substrate verapamil in the perfused rat heart.
In Langendorff-perfused rat hearts, the outflow concentration–time curve and inotropic response data were measured after a 1.5 nmol dose of [3H]-verapamil (infused within 1 min) in the absence and presence of the amiodarone (1 μM) in perfusate, as well as using a double dosing regimen (0.75 nmol in a 10 min interval). These data were analyzed by a PK/PD model.
Amiodarone failed to influence the rapid uptake and equilibrium partitioning of verapamil into the heart. The time course of the negative inotropic effect of verapamil, including the ‘rebound’ above the original baseline after the infusion of verapamil was stopped, could be described by a PK/PD tolerance model. Tolerance development (mean delay time, 12 min) led to a reduction in predicted steady-state effect (16%). The EC50 and E max values as estimated in single dose experiments were 16.4 ± 4.1 nM and 50.5 ± 18.9 mmHg, respectively.
The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.
Key wordsheart p-glycoprotein pharmacokinetic/pharmacodynamic model tolerance verapamil
coronary vascular resistance
left ventricular developed pressure
We thank the reviewers for insightful comments. Pakawadee Sermsappasuk is supported by a Royal Thai Government scholarship under the Committee Staff Development Project of Commission on Higher Education.
- 4.A. C. Powell, J. D. Horowitz, P. J. Kertes, Y. Hasin, M. L. Syrjanen, C. A. Henry, D. M. Sartor, and W. J. Louis. Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake. J. Cardiovasc. Pharmacol. 16:572–583 (1990).PubMedCrossRefGoogle Scholar
- 8.K. Meissner, B. Sperker, C. Karsten, H. M. Zu Schwabedissen, U. Seeland, M. Bohm, S. Bien, P. Dazert, C. Kunert-Keil, S. Vogelgesang, R. Warzok, W. Siegmund, I. Cascorbi, M. Wendt, and H. K. Kroemer. Expression and localization of P-glycoprotein in human heart: effects of cardiomyopathy. J. Histochem. Cytochem. 50:1351–1356 (2002).PubMedGoogle Scholar
- 9.A. J. Lazarowski, H. J. Garcia Rivello, G. L. Vera Janavel, L. A. Cuniberti, P. M. Cabeza Meckert, G. G. Yannarelli, A. Mele, A. J. Crottogini, and R. P. Laguens. Cardiomyocytes of chronically ischemic pig hearts express the MDR-1 gene-encoded P-glycoprotein. J. Histochem. Cytochem. 53:845–850 (2005).PubMedCrossRefGoogle Scholar
- 13.G. Speelmans, R. W. Staffhorst, F. A. De Wolf, and B. De Kruijff. Verapamil competes with doxorubicin for binding to anionic phospholipids resuling in increased internal concentrations and rates of passive transport of doxorubicin. Biochim. Biophys. Acta 1238:137–146 (1995).PubMedCrossRefGoogle Scholar
- 20.D. Z. D’Argenio and A. Schumitzky. ADAPT II User’s guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Biomedical Simulations Resource, Los Angeles, 1997.Google Scholar