Comparisons of pharmacokinetics and genetic polymorphisms between type 2 diabetic patients with and without edema conditions when treated with thiazolidinediones

Abstract

The purpose of this study were to determine the prevalence of thiazolidinediones (TZDs)-induces edema, the role of different genetic polymorphisms on TZDs-induced edema in type 2 diabetic patients, and to compare doses and pharmacokinetic (PK) parameters of pioglitazone between patients with and without edema conditions. Medical chart of 278 diabetic patients using TZD at Ramathibodi hospital were reviewed to determine the prevalence of TZDs-induces edema and the demographic factors which might influencing the risk of edema. 25 patients who came to follow-up treatment at the medical outpatient clinic and agree to participate were recruited for pharmacokinetic study, two blood samples were collected from each patient and were analyzed pioglitazone concentrations by HPLC-UV method, then, PK parameters were determined. Blood sample of 134 patients were analyzed for SNPs of endothelin-1 (ENDO1; rs5370) and epithelial sodium channel β subunit (SCNN1B; rs34241435) by Tag polymerase and LightCycler 480 SYBR Green I Master system. The prevalence of edema in patients using TZD combined with other anti-diabetic drugs identified in this study was 13.7% (15.1% for pioglitazone and 12.2% for rosiglitazone). Factors influencing the risk of edema in patients who were using TZD were age, sex, macrovascular diseases, ACEI use, high dose of TZD, and co-medication with insulin. The PK parameters of pioglitazone were not different between edema and non-edema groups. However, Ke, t1/2, and CL values of patients who were stabilized on high dose of pioglitazone were significantly different from those who were stabilized on low dose of pioglitazone. Lower Ke and CL were found in non-edema patients who stabilized on 15 mg dose of pioglitazone as compared to those who were stabilized on 30 mg dose of pioglitazone, lower dose of pioglitazone were therefore required for controlling blood glucose. This study found the rate of allele frequency of ENDO1 in Thai patients to be 32.1%, while no allele frequency could be found for SCNN1B. The polymorphisms frequency of ENDO1 showed no significantly different between edema and non-edema groups.