Antiaggregatory activity of hypoglycaemic sulphonylureas.
OBJECTIVE
Vascular complications observed in diabetes are often related to altered platelet functions. The most widely used hypoglycaemic drugs for treating Type II (non-insulin-dependent) diabetes mellitus are sulphonylurea derivatives. The purposes of this study were to evaluate the inhibitory effects of hypoglycaemic agents on platelet aggregation, to measure their lipophilicity and identify their structural parameters which assess their antiaggregatory activity.


METHODS
An antiaggregatory test in vitro was carried out for 13 sulphonylurea derivatives. Aggregation of platelets, incubated with the agents at concentrations varying from 7.5 to 480 micromol/l, was induced by 10 micromol/l ADP. Drug lipophilicity parameter, log k(w), was measured by gradient HPLC and the agents were subjected to molecular modelling.


RESULTS
The most pronounced inhibition of platelet aggregation was by glimepiride, gliclazide, gliquidone, glibenclamide and compound 2A. The IC(25) values were 15.9, 18.6, 20.4, 28.5 and 34.7 micromol/l, respectively. Quantitative structure-activity relationships indicate that antiaggregatory activity is mainly affected by electronic and not by lipophilic properties of the agents.


CONCLUSIONS
Glimepiride appeared to be a more potent ADP-induced platelet aggregation inhibitor in vitro than gliclazide. Antiaggregatory activity was shown for gliquidone and confirmed for glibenclamide. The QSAR analysis supports the hypothesis of a free radical mechanism of action of sulphonylurea derivatives previously suggested for gliclazide.
Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Poland.
D
D
Siluk
R
R
Kaliszan
P
P
Haber
J
J
Petrusewicz
Z
Z
Brzozowski
G
G
Sut
D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012016:Reference Values; D012907:Smoking; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D010975:Platelet Aggregation Inhibitors; D013453:Sulfonylurea Compounds; C057619:glimepiride