Abstract
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 minimised, 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.
Key words
Glimepiride - NIDDM - Glucose Clamp - Kidney Disease - Liver Disease
