Glimepiride (Amaryl) Half-Life
The apparent terminal half-life of glimepiride does not change across different patient populations and remains stable even in patients with renal impairment, though the FDA label notes that metabolite half-lives (M1 and M2) increase as renal function decreases. 1
Pharmacokinetic Parameters
The FDA drug label provides the following key pharmacokinetic data for glimepiride after intravenous dosing in healthy subjects 1:
- Volume of distribution (Vd): 8.8 L (113 mL/kg)
- Total body clearance (CL): 47.8 mL/min
- Protein binding: Greater than 99.5%
Glimepiride demonstrates linear pharmacokinetics across the 1-8 mg dose range, with clearance remaining unchanged after oral administration. 1
Metabolism and Excretion Characteristics
Glimepiride undergoes complete metabolism via oxidative biotransformation, primarily through cytochrome P450 2C9 to form the cyclohexyl hydroxy methyl derivative (M1), which is then further metabolized to the carboxyl derivative (M2) by cytosolic enzymes. 1
Approximately 60% of total radioactivity is recovered in urine within 7 days, with M1 and M2 accounting for 80-90% of urinary radioactivity, while 40% is recovered in feces with no parent drug recovered from either urine or feces. 1
Special Population Considerations
Renal Impairment
In patients with severe renal impairment (creatinine clearance <20 mL/min), the apparent terminal half-life for glimepiride itself does not change, but the half-lives for metabolites M1 and M2 increase significantly. 1 This is clinically reassuring because glimepiride lacks active metabolites that accumulate with decreased kidney function, and pharmacokinetics remain mainly unaltered in patients with renal disease. 2
Elderly Patients
A multiple-dose study using glimepiride 6 mg daily showed no significant differences in glimepiride pharmacokinetics between patients ≤65 years and those >65 years. 1 The mean AUC at steady state for older patients was approximately 13% lower, and weight-adjusted clearance was approximately 11% higher, but these differences were not clinically significant. 1
Obese Patients
While morbidly obese patients had lower Cmax and AUC compared to normal weight patients, the tmax, clearance, and volume of distribution were similar between groups, indicating no special dose consideration is required for obese patients. 1, 3
Clinical Implications
The stable half-life and lack of active metabolite accumulation contribute to a lower risk of prolonged hypoglycemia, particularly important in patients with renal impairment or elderly patients. 2 This pharmacokinetic profile distinguishes glimepiride from first-generation sulfonylureas and makes it a safer option in these vulnerable populations. 2