Table 3.

Pgp-mediated DDIs of commonly prescribed cardiovascular ion channel inhibitors

Drug	Sub.a	Inh.b	Ind.	Digoxin PK	Other	References
amiodarone	non	6 μM	NA	AUC: increases 66%c CLR: no change Cmax: increases 78%c VD: no change or decreases	apixaband dabigatrand digitoxine daunorubicinf flecainidef rivaroxaband	(55, 56, 58, 60–62)
amlodipine	non to good	NA	NA	Css: No change	simvastating	(65, 66, 68)
digoxin	good	-	Yes	-	quinidineh	(61, 69, 70, 72, 73, 78)
diltiazem	weak	36 μM	NA	AUC: increases 34%c Cmax: increases 31%c	quinidineh	(61, 64, 82).
dronedarone	non	NA	NA	AUC: increases 150% CLR: decreases 60%		(59)
flecainide	good	NA	NA	Cavg: increased ~20%		(57, 84)
mibefradil	non	7.5 μM	NA	AUC: increases 31% Cmax: increases 41%	atorvastating	(61, 87)
nicardipine	non	<1 μM	NA	AUC: increases 6% Cmax: increases 6%		(61, 64)
nifedipine	non	<1 μM	NA	AUC: increases 21%c Cmax: increases 5%c		(61, 64)
ouabain	X	No	Yes	NA		(71, 78, 80, 81)
phenytoin	non to good	NA	NA	AUC: decreases 23% CL: increases 27% CLR: no change VD: no change	paclitaxeli	(90, 91, 93, 96)
quinidine	good	21 μM	Yes	AUC: increases 121%c CL: decreases 56% CLR: decreases 51% Cmax: increases 75% F: increases 16% t1/2: decreases 47% VD: decreases 38%	edoxaband fentanylj flecainidef methadonej	(57, 61, 70, 72, 98–102)
verapamil	non to good	1–200 μM	NA	AUC: increases 51% CL: decreases 34% CLH: decreases 62% CLR: decreases 21% Cmax: increases 44% t1/2: increases 31% VD: decreases 23%	colchicinek dabigatrand prazosinl quinidineh vinblastinek	(61, 64, 75, 86, 106, 112–114)

^aClassification of a drug as a non-substrate (non), weak substrate (weak), good substrate (good) or non-ligand (X) to Pgp. A non-substrate had an efflux ratio = 1, a weak substrate had an efflux ratio >1 and <2, a good substrate had an efflux ratio >2 and a non-ligand was neither a substrate or inhibitor for Pgp.

^bIn vitro inhibition concentration range of Pgp-mediated digoxin transport by the drug.

^cAverage pharmacokinetic values.

Abbreviations:-, not applicable; AUC, area under the curve; C_avg, average drug plasma concentration; C_ss, steady-state drug plasma concentration; CL, total clearance CL_H, extrarenal clearance; CL_R, renal clearance; C_max, peak drug plasma concentration; DEA, monodesethyl-amiodarone; Ind., inducer; Inh., inhibitor; NA, not available; Sub., Substrate; t_1/2, terminal elimination half time; V_D, apparent volume of distribution.

^dThe more severe ADRs were myopathy (115),

^edigitalis-associated toxicities (116),

^fcardiotoxicity (117, 118),

^gbleeding and thrombosis(119),

^hthrombocytopenia (120),

ⁱcardiac arrest (121),

^jrespiratory depression (122, 123),

^kneutropenia (124, 125) and

^lorthostatic hypotension (126)^l.