Sign Out
PHARMACOLOGY: Pharmacodynamics: Glimepiride is a blood sugar-lowering agent belonging to the sulfonylurea group. The decrease in blood sugar is achieved principally by means of the stimulation of insulin release from pancreatic beta cells. This effect is predominantly based on improved responsiveness of these cells to the physiological glucose stimulus. Glimepiride augments the normal action of insulin on peripheral glucose uptake. Moreover, it mimics such action as well as the glucose output of the liver.
Metformin is a biguanide derivative of guanidine, used for treating type II diabetes mellitus. Defects which cause hyperglycaemia and type II diabetes mellitus include alterations in pancreatic insulin secretion, elevations in hepatic glucose production, and peripheral insulin resistance. Metformin acts via mechanisms by reduction in hepatic glucose production, reduction in intestinal glucose absorption and increased insulin sensitivity (improved peripheral glucose uptake and utilization).
Pharmacokinetics: Glimepiride pharmacokinetics (Tmax and AUC) after meal was similar between a sustained-release formulation of Amaryl M SR 2/500 mg and an immediate-release formulation of single Amaryl M 2/500 mg or B.I.D. Amaryl M 1/250 mg. Meanwhile, metformin Tmax was delayed in sustained-release formulation compared to immediate-release formulation, but its elimination half-life was not prolonged. The extent of metformin exposure after meal was lower in sustained-release formulation than in immediate-release formulation and its B.I.D. treatment in divided doses by 14% and 23% on average, respectively. This effect on exposure is not considered clinically significant as there was no significant difference in safety between treatment groups.
Toxicology: Preclinical safety data: Metformin: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately three times the maximum recommended human daily dose on a body surface area basis. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. However, an increased incidence of benign stromal uterine polyps was seen in female rats treated with 900 mg/kg/day.
No evidence of a mutagenic potential of metformin was found in Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), chromosomal aberration test (human lymphocytes), or in vivo micronuclei formation test (mouse bone marrow).
Fertility of male or female rats was unaffected by metformin administration at doses as high as 600 mg/kg/day, or approximately two times the maximum recommended human daily dose on a body surface area basis.
Glimepiride: In subchronic and chronic toxicity studies in rats, mice and dogs, a decline in serum glucose as well as a degranulation of the beta cells of the pancreas were noted; these where shown to be, in principle, reversible and are regarded as signs of the pharmacodynamic effect. In a chronic toxicity study in dogs, two of the animals receiving the highest dose (320 mg/kg body weight) developed cataracts. In vitro studies in the bovine lens and investigations in rats demonstrated no cataractogenic or co-cataractogenic potential.
Lifetime studies in rats revealed no carcinogenic potential. In mice, there was an increased incidence of islet cell hyperplasia and of islet cell adenomas; these are regarded as resulting from the chronic stimulation of the beta cells. Glimepiride did not show any mutagenic or genotoxic effects.
Administration to rats revealed no effects on fertility, course of pregnancy or delivery. Fetuses delivered by caesarean section were slightly retarded in growth. In spontaneously born progeny whose mothers had been treated with high doses, anomalies of the humerus, femur, shoulder and hip joint were observed. Oral administration in the late phase of pregnancy and/or during lactation led to increased numbers of fetal deaths and to the same limb deformities.
Glimepiride had no recognizable effects on the rearing, physical development, functional and learning behaviour, memory or fertility of the progeny. Glimepiride is ingested by the offspring in breast milk; high doses given to mother rats cause hypoglycaemia in suckling young rats.
Malformations (e.g. eye malformations, fissures, and bone anomalies) occurred in rats and rabbits and, in rabbits only, the numbers of abortions and intrauterine deaths were increased.
All reproduction toxicology findings are probably due to the pharmacodynamic effects of excessive doses and are not substance specific.
