Modeling cardiac uptake and negative inotropic response of verapamil in rat heart: effect of amiodarone.
OBJECTIVE
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.


METHODS
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 microM) 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.


RESULTS
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 Emax values as estimated in single dose experiments were 16.4+/-4.1 nM and 50.5+/-18.9 mmHg, respectively.


CONCLUSIONS
The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.
Sermsappasuk
Pakawadee
P
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, D-06097, Halle, Germany.
Abdelrahman
Osama
O
Weiss
Michael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000465:Algorithms; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D015233:Models, Statistical; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000493:pharmacokinetics* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D014700:Verapamil; D000638:Amiodarone