What are the pharmacokinetics of digoxin?

Pharmacokinetics of Digoxin

Digoxin has a bioavailability of 60-80%, an elimination half-life of 36-48 hours, and is primarily excreted unchanged in the urine (50-70%), with metabolism primarily occurring via gut bacteria rather than the CYP450 system. 1

Absorption

• Oral bioavailability: 60-80% 1, 2
• Onset of effect: 1-3 hours after oral administration 1
• Peak plasma concentrations: Reached within 1-3 hours 2
• Food effects: When taken with meals, absorption rate is slowed but total amount absorbed usually remains unchanged 2
• High-fiber meals (especially bran) may reduce absorption 2

Distribution

• Volume of distribution: Large, as digoxin is concentrated in tissues 2
• Distribution correlates best with lean body weight, not total body weight 2
• Plasma protein binding: Approximately 25% 2
• Crosses both blood-brain barrier and placenta 2
• Initial tissue distribution phase: 6-8 hours after administration 2
• Steady-state post-distribution serum concentrations correlate with pharmacologic effects 2

Metabolism

• Only about 16% of digoxin is metabolized 2
• Primary metabolism occurs via gut bacteria, not the CYP450 system 1, 2
• In approximately 10% of patients, colonic bacteria convert orally administered digoxin to inactive reduction products (e.g., dihydrodigoxin) 2
• Antibiotics can disrupt gut bacteria, potentially increasing serum digoxin levels up to two-fold 2

Excretion

• Elimination half-life: 36-48 hours in patients with normal renal function 1, 2
• Primary route: 50-70% excreted unchanged in urine 1, 2
• Renal excretion is proportional to glomerular filtration rate and largely independent of urine flow 2
• Half-life in anuric patients: Prolonged to 3.5-5 days 2
• Digoxin is not effectively removed by dialysis, exchange transfusion, or cardiopulmonary bypass 2

Special Populations and Considerations

Renal Function

• Clearance primarily correlates with renal function (creatinine clearance) 2
• Dose adjustments required in renal impairment 2
• Reduced renal function increases half-life and risk of toxicity 2

Elderly Patients

• Lower doses (0.125 mg daily or every other day) should be used if patient is >70 years of age 1
• Elderly patients have reduced renal function, decreased lean body mass, and higher risk of toxicity 1

Sex Differences

• Women have lower volume of distribution for hydrophilic drugs like digoxin 1
• Women may reach higher peak plasma concentrations (Cmax) and experience greater effects 1
• Women have lower renal blood flow, estimated glomerular filtration rate (eGFR), and tubular secretion/reabsorption 1

Drug Interactions

P-glycoprotein Interactions

• Digoxin is a substrate for P-glycoprotein (P-gp) efflux transporter 1
• High-dose atorvastatin (80 mg) can increase digoxin Cmax by 20% and AUC by 15% through P-gp inhibition 1
• Lower doses of atorvastatin (10 mg) do not significantly alter digoxin pharmacokinetics 1

Other Important Interactions

• Amiodarone, clarithromycin, dronedarone, erythromycin, itraconazole, cyclosporine, propafenone, verapamil, and quinidine can increase serum digoxin concentrations 1
• Digoxin dose should be reduced when these medications are initiated 1
• Hypokalaemia, hypomagnesaemia, or hypothyroidism can increase risk of toxicity even at therapeutic serum levels 1

Therapeutic Drug Monitoring

• Target serum concentration: 0.5-0.9 ng/mL 1
• Toxicity commonly associated with levels >2 ng/mL 1
• Sampling should be done just before the next scheduled dose or at least 6-8 hours after the last dose 2
• On once-daily dosing, concentration will be 10-25% lower when sampled at 24 versus 8 hours 2

Clinical Pearls

• Loading doses are not necessary when initiating therapy for chronic heart failure 2
• Maintenance doses should be calculated based on lean (ideal) body weight 2
• Digoxin is not dependent on the CYP450 system 1
• Exercise may temporarily decrease serum digoxin concentration due to increased binding to skeletal muscle, without affecting clinical efficacy 2

By understanding these pharmacokinetic properties, clinicians can optimize digoxin dosing to maximize efficacy while minimizing the risk of toxicity in patients with heart failure or atrial fibrillation.