Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes.
OBJECTIVE
Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes.


METHODS
Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles.


RESULTS
The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively.


CONCLUSIONS
Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect.
Davis
T M
TM
University of Western Australia, Department of Medicine, Fremantle Hospital, Fremantle, Western Australia, Australia. tdavis@cyllene.uwa.edu.au
Daly
F
F
Walsh
J P
JP
Ilett
K F
KF
Beilby
J P
JP
Dusci
L J
LJ
Barrett
P H
PH
D000328:Adult; D000368:Aged; D001315:Australia; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D005260:Female; D005907:Gliclazide / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period / Q000502:physiology; D044465:White People
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D005907:Gliclazide