Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients.
The pharmacokinetics of the sulfonylurea, glimepiride, in risk groups of NIDDM patients are reviewed with regard to pharmacokinetic-effect relationships. A variety of factors, such as regulatory processes, glucose absorption, insulin sensitivity, might prevent the definition of a clear concentration-effect relationship for sulfonylureas. However, when these processes are minimized, as with the glucose clamp technique, such relationships can be defined. This is true for glibenclamide or glimepiride, for which saturation of effect is apparent in the upper therapeutic dose range in healthy subjects. However, pharmacokinetic-pharmacodynamic relationships are less readily defined during long-term treatment of NIDDM patients. In kidney or liver disease, the hypoglycemic effect of sulfonylureas can be increased and prolonged, mainly due to a decrease in insulin metabolism or of hepatic glucose output; the risk of hypoglycemia is increased. The pharmacokinetics of most sulfonylureas have not been well characterised in patients with kidney or liver disease. Generally, sulfonylureas are eliminated by renal excretion of metabolites, some of which have similar pharmacological activity to the parent drug e.g. glibenclamide, chlorpropamide, tolbutamide. In renal disease, elimination of these metabolites can be impaired. In 31 NIDDM patients with kidney disease, elimination of unchanged glimepiride was greater in patients with more severe renal disease, probably due to a decrease in the plasma protein-bound fraction. Elimination of the renally excreted metabolites was also impaired in the same group of patients. 12 of 16 NIDDM patients with kidney disease who continued glimepiride treatment for three months maintained fasting blood glucose levels of less than 9.99 mmol/l at a daily dose of 1-6 mg, the typical dose range for patients with normal renal function. Pharmacokinetic data on sulfonylureas are generally inconsistent in cirrhotic patients. In 11 patients with liver disease, the pharmacokinetics of glimepiride were similar to those of healthy volunteers. In conclusion, pharmacokinetics, pharmacodynamics and their relationships can be defined for glimepiride under controlled conditions. Such information is lacking for many commonly used sulfonylureas in risk group NIDDM patients. Studies described here show that the pharmacokinetics of glimepiride are altered in renal disease but may not be seriously affected in patients with liver disease.
Hoechst AG, Frankfurt, Germany.
B
B
Rosenkranz
D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007674:Kidney Diseases / Q000150:complications / Q000378:metabolism; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride