In vitro cell model Efflux Ratio or Net transport Digoxin Detection Ref.
L-MDR1 R(B-A/A-B) ≈ 8
After addition of verapamil, vimblastine or quinidine (20 µM): R(B-A/A-B) ≈ 2		 LSC [123]
  Results given by net transport [Papp (B-A) - Papp (A-B)]: > 20 pmol/mg
After addition of cyclosporin A (5 or 10 µM): < 10 pmol/mg		 LSC [124]
  R(B-A/A-B) ≈ 3.8
In presence of quinidine, verapamil or vincristine (all 20 µM):
Papp (B-A) of digoxin decrease by 51%, 45% and 59%;
Papp (A-B) of digoxin increase by 75%, 32% and 46%.		 - [125]
  R(B-A/A-B) > 5
In LLC-PK1: R(B-A/A-B) < 2		 LSC [126]
  Caco-2 R(B-A/A-B) ≈ 4 LSC [127]
R(B-A/A-B) ≈ 4.24
After addition of vincristine (P-gp inducer) at 10 µM: R(B-A/A-B) ≈ 10.1		 LSC [128]
MDCK-MDR1 R(B-A/A-B) ≈ 25.5
After addition of verapamil (200 µM): R(B-A/A-B) ≈ 1.3
In MDCK (non transfected): R(B-A/A-B) ≈ 5.2
In MDCK (non transfected) with verapamil: R(B-A/A-B) ≈ 2.2		 LSC [130]
R(B-A/A-B) ≈ 33.6 LSC [69]
R(B-A/A-B) ≈ 51.8 LSC [131]
Non-clinical in vivo Administration Results in relation to wild mice Digoxin Detection Ref.
Abcb1a (-/-) mice IV, 1 mg/Kg Brain concentration 35.3 fold higher LSC [126]
IV, 0.2 mg/Kg Faecal excretion 75% lower
Renal excretion 120% increased		 LSC [132]
Oral, 0.2 mg/Kg Faecal excretion 48% lower
Renal excretion 240% increased
Abcb1a/b
(-/-) mice		 IV, 1 mg/Kg Knockout/wild ratios:
Brain content: 27.2; Adrenal gland: 6.2;
Ovaries: 7.7
Higher plasma level (P < 0.02)
Lower intestinal excretion (P < 0.02)
Lower biliary excretion (P < 0.05)		 LSC [70]
Oral 0.05 mg/Kg Brain to plasma ratio 27.8 fold increased LSC [132]
IV, 0.05 mg/Kg Brain to plasma ratio 10-fold increased
IP, 0.20 mg/Kg Kidney concentration approximately 30-fold higher
Serum concentration approximately 2-fold higher, but not statistically different		 Fluorescence polarization immunoassay [133]
Human Clinical studies Co-administered drug Effect on pharmacokinetics of digoxin Digoxin Detection Ref.
  Itraconazole Renal clearance decreased 20% AUC increased 50% - [134]
  Verapamil Biliary clearance diminished 43%
Plasma concentration increased 44%		 - [69,135]
  Quinidine Biliary clearance diminished 42% HPLC [69]
  Rifampin Decreased AUC more than 15% Fluorescence polarization immunoassay [136]
Table 5: In vitro and in vivo studies in which digoxin was shown as a substrate of P-gp. AUC, area under the curve; Cmax., maximum plasma concentration; IV, intravenous; LLC-PK1, porcine kidney tubular cell line; L-MDR1, porcine kidney tubular cell line transfected with human MDR1 gene; LC, liquid chromatography; LSC, liquid scintillation counter; MDCK, Madin-Darby canine kidney cell line; MDCK-MDR1, Madin-Darby canine kidney cell line transfected with human MDR1 gene; Papp, apparent permeability; R(B-A/A-B), efflux ratio given by the ratio between apparent permeability in efflux (B-A) and absorption (A-B) directions.
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