Amaryl

[Glimepiride]

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.

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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 II C9 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 NIDDM are summarized below: Volunteers Patients with NIDDM
Cmax (ng/mL) Single DoseMean±SD Single Dose(Day 1)Mean±SD Multiple Dose(Day 10)Mean±SD
1 mg 103 ± 34 (12) --- ---
2 mg 177 ± 44 (12) --- ---
4 mg 308 ± 69 (12) 352 ± 222 (12) 309 ± 134 (12)
8 mg 551± 152 (12) 591 ± 232 (14) 578 ± 265 (11)
Tmax (h) 2.4 ± 0.8 (48) 2.5 ± 1.2 (26) 2.8 ± 2.2 (23)
CL/f (mL/min) 52.1 ± 16.0 (48) 48.5 ± 29.3 (26) 52.7 ± 40.3 (23)
Vd/f (L) 21.8 ± 13.9 (48) 19.8 ± 12.7 (26) 37.1 ± 18.2 (23)
T1/2 (h) 5.3 ± 4.1 (48) 5.0 ± 2.5 (26) 9.2 ± 3.6 (23)
( ) = No. of subjectsCL/f=Total body clearance after oral dosingVd/f=Volume of distribution calculated after oral dosing

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