Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes

Aims Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Ca ucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. Methods Subjects were on a stable dose of 80 mg gliclazide twice daily, too k 160 mg on the morning of study and had a standard breakfast. No further g liclazide was given over the next 48 h. Regular blood samples were drawn fo r serum glucose, insulin and gliclazide assay. Gliclazide was measured usin g h.p.l.c. Noncompartmental analysis was used to describe primary data. A m ulticompartment 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 durat ion, body mass index and glycated haemoglobin. Noncompartmental analysis re vealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer t ime to maximum concentration (t(max)) for glucose amongst the Aborigines (2 .6 +/- 0.4 vs 2.2 +/- 0.3 h in Caucasians; P = 0.024). Gliclazide t(max) ex hibited a skewed unimodal distribution and was not associated with gliclazi de maximum concentration, or glucose or insulin responses. Most patients ha d a serum gliclazide profile suggestive of enterohepatic recirculation and/ or biphasic absorption. Model-derived estimates of the extent of putative e nterohepatic recirculation were 30% and 20% of dose in Caucasians and Abori gines, respectively. Conclusions Gliclazide is equally effective in Caucasian and Aboriginal dia betic 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 hy poglycaemic effect.