Metformin Duration of Action
Metformin has a plasma elimination half-life of approximately 6.2 hours, with steady-state plasma concentrations reached within 24-48 hours of regular dosing, requiring twice-daily or once-daily (extended-release) administration to maintain therapeutic effect. 1
Pharmacokinetic Profile
Immediate-Release Formulation
- Plasma half-life is 6.2 hours, while the blood elimination half-life is approximately 17.6 hours due to erythrocyte distribution 1
- Peak plasma concentrations (Tmax) occur at approximately 2-3 hours after oral administration 1, 2
- Approximately 90% of absorbed drug is eliminated via renal route within 24 hours, with renal clearance approximately 3.5 times greater than creatinine clearance 1
- Steady-state is achieved within 24-48 hours of regular dosing, with plasma concentrations generally <1 μg/mL 1
Extended-Release Formulation
- Peak plasma concentrations occur later at a median of 7 hours (range 4-8 hours) after administration 1, 3
- The extended-release formulation provides slower, prolonged absorption in the upper gastrointestinal tract, permitting once-daily dosing 3, 4
- No drug accumulation occurs with multiple-dose administration (accumulation ratio = 1.0) 3
- The extent of absorption (AUC) is equivalent between extended-release and immediate-release formulations at the same total daily dose 1, 3
Clinical Dosing Implications
Standard Dosing Frequency
- Immediate-release requires twice-daily or thrice-daily dosing due to the 6.2-hour plasma half-life to maintain therapeutic concentrations throughout the day 1, 2
- Extended-release permits once-daily dosing, typically administered with the evening meal or at bedtime 5, 6
Renal Function Considerations
- In patients with impaired renal function, both plasma and blood half-life are prolonged and renal clearance is decreased, necessitating dose adjustments 1
- For eGFR 30-44 mL/min/1.73m², reduce dose to half the maximum (typically 500-1000 mg daily) and monitor kidney function every 3-6 months 5, 7, 6
- For eGFR <30 mL/min/1.73m², metformin is contraindicated and must be discontinued immediately 5, 7, 6
- Renal clearance of metformin is highly correlated with creatinine clearance, making kidney function the primary determinant of drug elimination 2
Important Clinical Caveats
Tissue Distribution
- The 17.6-hour blood half-life suggests erythrocyte mass serves as a distribution compartment, which may have implications for slow elimination phases 1, 2
- A slow elimination phase exists beyond the initial 6.2-hour plasma half-life, with potential for gradual accumulation in peripheral tissues during chronic therapy 2
Monitoring Requirements
- Monitor kidney function at least annually when eGFR ≥60 mL/min/1.73m², or every 3-6 months when eGFR <60 mL/min/1.73m² 5, 7
- Monitor vitamin B12 levels in patients on metformin >4 years due to risk of deficiency 5, 8
- Implement "sick day rules" to temporarily discontinue metformin during serious intercurrent illness that increases acute kidney injury risk 7, 6