Duration of Action of Metformin
Metformin has a plasma elimination half-life of approximately 6.2 hours after oral administration, requiring 2-3 times daily dosing for immediate-release formulations, while extended-release formulations maintain steady-state concentrations with once-daily dosing. 1
Pharmacokinetic Profile
Immediate-Release Metformin
- Plasma half-life: 6.2 hours following oral administration in patients with normal renal function 1
- Blood half-life is approximately 17.6 hours, suggesting erythrocyte mass serves as a distribution compartment 1
- Steady-state plasma concentrations are reached within 24 to 48 hours of initiating therapy 1
- Approximately 90% of absorbed drug is eliminated via renal route within the first 24 hours 1
- Due to the 6.2-hour half-life, immediate-release formulations require 2-3 times daily dosing to maintain therapeutic levels 2
Extended-Release Metformin
- Time to maximum plasma concentration (Tmax) is 7 hours (range 4-8 hours) compared to 3 hours for immediate-release 1
- Once-daily dosing is sufficient to maintain steady-state concentrations 2
- The mean accumulation ratio is 1.0, indicating no drug accumulation with multiple-dose administration 1, 3
- Extended-release formulation is typically administered with the evening meal or at bedtime 2
Impact of Renal Function on Duration of Action
Normal Renal Function (eGFR ≥60 mL/min/1.73m²)
- Standard half-life of 6.2 hours applies 1
- Renal clearance is approximately 3.5 times greater than creatinine clearance, with tubular secretion being the major elimination route 1
- No dose adjustment required 2, 4
Impaired Renal Function
- The plasma and blood half-life of metformin is significantly prolonged as renal function declines, with renal clearance decreasing proportionally to eGFR 2
- In elderly patients, half-life is prolonged compared to younger adults, primarily due to declining renal function 2
- Patients with moderate renal impairment (eGFR 30-44 mL/min/1.73m²) experience prolonged drug elimination, necessitating dose reduction to maximum 1000 mg daily 2
- Severe renal impairment (eGFR <30 mL/min/1.73m²) leads to toxic accumulation due to markedly prolonged half-life 2
Clinical Implications
Dosing Frequency Requirements
- Immediate-release: 2-3 times daily due to 6.2-hour half-life 2
- Extended-release: Once daily (typically evening) maintains adequate steady-state levels 2, 1
- Maximum daily dose is 2000-2550 mg for patients with normal renal function 2
Therapeutic Levels
- Steady-state plasma concentrations are generally <1 μg/mL 1
- Therapeutic levels may be 0.5-1.0 mg/L in fasting state and 1-2 mg/L after a meal 5
Critical Safety Consideration
- The relatively short half-life (6.2 hours) in normal renal function means metformin is rapidly cleared, but this becomes a significant safety issue when renal function declines 1
- Metformin should be held during acute illness that may impair renal function, as reduced clearance leads to accumulation and substantially increased risk of fatal lactic acidosis 2
- Drug should not be restarted until eGFR has recovered to ≥30 mL/min/1.73m² and remains stable 2