Pharmacokinetic Stereoselectivity of Troglitazone, an Antidiabetic Agent, in the Kk Mouse

Abstract

Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non‐insulin‐dependent diabetes, was examined. In the incubation experiments at 37 °C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1·3‐fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2·5‐fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low. ©1997 by John Wiley & Sons, Ltd.

Chalcone-Based Aryloxypropanolamine as a Potential Antidiabetic and Antidyslipidaemic Agent

“…The issue of chirality to avoid unnecessary drug burden on the body has also emerged as a factor in decision making for the selection of lead compound for further studies in drug discovery process, as enantiomers often differ in their pharmacological activity, toxicity and pharmacokinetic characteristics [25][26][27] . This prompted us to undertake pharmacokinetic study of racemic compound along with resolved individual optical isomers in laboratory animals.…”

The Role of Pharmacogenetics in the Treatment of Diabetes Mellitus / ULOGA FARMAKOGENETIKE U LEČNJU DIJABETES MELITUSA

“…Troglitazone is metabolized into sulphate and glucuronide conjugates and a quinine-type metabolite (90,91), and its metabolism appears to inhibit activities of other cytochrome P450 enzymes, suggesting it may interact with other medications. In contrast, pioglitazone is metabolized into five metabolites, mainly by CYP3A4, CYP2C8 and CYP2C9, and three of these metabolites appear to be active (92).…”

“…Together, these changes lead to a decrease in circulating free fatty acids (FFA), which reduces FFAinduced insulin resistance in skeletal muscles. It has been shown as well that TZD therapy alters concentrations of other adipokines, such as leptin, adiponectin and TNF-a (111)(112)(113)(114). Data also suggests that troglitazone-induced changes in insulin sensiti vity are not associated with changes in total adipo nectin concentration, but with changes in the high molec ular weight subfraction (113).…”

Determination of troglitazone stereoisomers in rat plasma using semi-micro HPLC with electrochemical detection

“…In general, separation of stereoisomers has become very important in analytical chemistry, especially in the pharmaceutical and biological fields, because some stereoisomers of racemic drugs have quite different pharmacokinetic properties and different pharmacological or toxicological effects [7][8][9]. Furthermore, stereoselectivity was predicted for the pharmacokinetics and metabolism of troglitazone in humans [10][11][12]. That is one of the most important reasons why the regulatory authorities demand more stringent investigations for evaluating the safety and effectiveness of drugs containing asymmetric centers.…”