MDR1-Mediated Interaction of Digoxin with Antiarrhythmic or Antianginal Drugs.

Abstract

Digoxin, a cardiac glycoside, is mainly prescribed for patients with congestive heart failure. Cardiac arrhythmia sometimes occurs in patients who are taking digoxin, 1,2) and thus antiarrhythmic drugs were often co-administrated with digoxin. In fact, antiarrhythmic or antianginal drugs were also prescribed for 25% and 21% of patients taking digoxin, respectively, in our hospital.3) Digoxin is well known to have only a narrow therapeutic concentration range (trough: 0.5-2.0 ng/ml), and to be prone to drug-drug interaction.4) Clinical reports suggested that the serum concentration of digoxin was elevated by amiodarone, 5-7) quinidine, [8][9][10] verapamil 11,12) and nicardipine, 13) and the daily dose of digoxin is adjusted based on a sophisticated serial monitoring of serum digoxin concentration.Digoxin has been found to be mainly excreted by tubular secretion and glomerular filtration, 4,14) and tubular secretion has been demonstrated to be mediated via MDR1 by using LLC-GA5-COL150 cells, which were established by transfection of MDR1 cDNA into porcine kidney epithelial LLC-PK 1 cells. 15,16) Herein, the effects of amiodarone, its active metabolite monodesethyl-amiodarone (DEA) amd quinidine on the transport of [ 3 H]digoxin was examined using LLC-GA5-COL150 cells to elucidate whether MDR1 was responsible for the drug interaction between digoxin and amiodarone or quinidine found in clinical use. The possibility of interaction with other antiarrhythmic drugs, cibenzoline, lidocaine, disopyramide and mexiletin, and antianginal drugs, dipyridamole and isosorbide, was also examined. These are selected because they are more frequently used with digoxin compared with others, at least in our hospital. MATERIALS AND METHODS ChemicalsCibenzoline was a gift from Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). DEA was a gift from Taisho Pharmaceutical Co., Ltd. (Tokyo, Japan). Amiodarone, mexiletin and quinidine were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Disopyramide, lidocaine, dipyridamole and colchicine were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Isosorbide was purchased from Alexis Co. (San Diego, CA, U.S.A.). [3 H]Digoxin (595.7 GBq/mmol) was purchased from Du Pont-New England Nuclear (Boston, MA, U.S.A.). Unlabeled digoxin was purchased from Aldrich Chemical Co. (Milwaukee, WI, U.S.A.). All other chemicals were of the highest purity available.Culture of LLC-PK 1 and LLC-GA5-COL150 Cells LLC-GA5-COL150 cells were established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK 1 cells.15,16) LLC-PK 1 and LLC-GA5-COL150 cells were maintained in the culture medium consisting of Medium199 (Dainippon Pharmaceutical Co. Ltd., Osaka, Japan) supplemented with 10% fetal bovine serum (FBS; BioWhittaker, Walkersville, MD, U.S.A.), with no antibiotics. Colchicine was also added to a final concentration of 150 ng/ml only for LLC-GA5-COL150 cells. LLC-PK 1 (1.0ϫ10 6 cells/100 mm 2 ) and LLC-GA5-COL150 cells (1.5ϫ10 6 cells/100 mm 2 ) were seeded on plastic cu...

Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay

“…Fromm et al (1999) have shown that 5 M quinidine effectively inhibits P-gp-mediated transport of digoxin by approximately 57% in the Caco-2 MDR1-transfected cell line. Kakumoto et al (2002) also demonstrated that quinidine inhibits the transport of digoxin in MDR1-overexpressing LLC-GA5-COL150 cells with an estimated IC 50 value of 9.52 M. Here, we tested whether coperfusion of quinidine in isolated perfused rat livers could inhibit the P-gp-mediated transport of digoxin. In the liver, absorbed compounds enter the hepatocytes from the sinusoidal blood and then the drugs are either biotransformed, transported/diffused back into blood, or eliminated via biliary secretion.…”

Pharmacokinetic Characteristics of Amiodarone in Long-Term Oral Therapy in Japanese Population

“…It is well known that the activities of CYP3A4 and P-glycoprotein contribute to the bioavailability of drugs, and the bioavailability of amiodarone is low. On the other hand, desethylamiodarone inhibits the activities of both CYP3A4 and P-glycoprotein 7,23) thus it is suggested that the bioavailability of amiodarone is gradually increased with time in subjects receiving long-term amiodarone therapy, and individual variation of the clearance decreases in subjects receiving long-term amiodarone therapy.…”

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

“…The likely cause is the inhibition of P-glycoprotein activity by amiodarone [34]. During the use of amiodarone, the dose of digoxin should be reduced by 30-50% [35].…”