Distribution. After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.

Metabolism. Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (m²). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to m² by one or several cytosolic enzymes. M1, but not m², possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.

Excretion. When ¹⁴C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and m² accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and m² (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

Pharmacokinetic Parameters. The pharmacokinetic parameters of glimepiride obtained from a single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose-proportionality (4 and 8 mg) study in patients with Type 2 diabetes are summarized below:

These data indicate that glimepiride did not accumulate in serum, and the pharmacokinetics of glimepiride were not different in healthy volunteers and in Type 2 diabetic patients. Oral clearance of glimepiride did not change over the 1-8-mg dose range, indicating linear pharmacokinetics.

Variability. In normal healthy volunteers, the intra-individual variabilities of Cmax, AUC, and CL/f for glimepiride were 23%, 17%, and 15%, respectively, and the inter-individual variabilities were 25%, 29%, and 24%, respectively.

Special Populations

Geriatric. Comparison of glimepiride pharmacokinetics in Type 2 diabetic patients ≤ 65 years and those > 65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients.

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