The digoxin-amiodarone interaction

Abstract

To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4-8 months. Mean (+/- SD) peak plasma digoxin concentration rose from 1.55 +/- 0.6 microgram /1 prior to amiodarone therapy to 2.85 +/- 1.3 micrograms/1 after 1 week of combined therapy (p less than 0.01). Mean AUC also rose from 7.2 +/- 2.1 micrograms/1.h to 12.1 +/- 6.4 micrograms/1.h (p less than 0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4-8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses. This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.

Edoxaban Transport via P-Glycoprotein Is a Key Factor for the Drug’s Disposition

“…However, the intestine was considered to be a primary tissue for the P-gp-mediated DDIs, because in general, intestinal concentration of P-gp inhibitors is projected to be much higher than that in plasma following oral administration. This explanation was exemplified by the DDI documented between digoxin and amiodarone, during which amiodarone increased the C max and AUC of digoxin without affecting its renal CL (Robinson et al, 1989). The total plasma concentration of amiodarone did not reach the IC 50 value against P-gp.…”

Digoxin Is Not a Substrate for Organic Anion-Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but Is a Substrate for a Sodium-Dependent Transporter Expressed in HEK293 Cells

“…Most clinical investigations conducted to date have focused on P-gpmediated drug interactions [e.g., DDI studies involving digoxin and amiodarone (Robinson et al, 1989) and quinidine (Rameis, 1985)]. However, two publications suggest that, in addition to P-gp, digoxin is also a substrate for OATP1B3 (Kullak-Ublick et al, 2001) and OATP4C1 (Mikkaichi et al, 2004;Chu et al, 2007).…”

“…Several comedications that are commonly prescribed in the cardiovascular field are inhibitors of P-gp, such as quinidine, cyclosporine, and amiodarone (Gillis and Kates, 1984;Robinson et al, 1989;De Lannoy et al, 1992;Weiss et al, 2003). These drugs can elevate circulating levels of digoxin via inhibition of P-gp and as such require dose adjustments (Lesko, 1989).…”

Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions

“…There are several comedications that increase digoxin exposure greater than twofold such as valspodar (Kovarik et al, 1999), dronedarone [MULTAQ (dronedarone), 2009], quinidine (Rameis, 1985), amiodarone (Robinson et al, 1989), and cyclosporine (Dorian et al, 1988), which is much greater than the theoretical increase in digoxin exposure if only intestinal P-gp was inhibited (;42% increase based on digoxin bioavailability increasing from 70 to 100%). It is likely that inhibition of digoxin uptake in or efflux from the liver or kidney is also a possible contributor to certain DDIs.…”