Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

Abstract

-Rosiglitazone maleate (RGM) is widely used for improving insulin resistance. RGM is a moderate inhibitor of cytochrome P450 2C8 (CYP2C8) and is also mainly metabolized by CYP2C8. The aim of this study was to determine whether the effect of RGM on CYP2C8 is altered by co-treatment with other drugs, and whether amlodipine camsylate (AC) changes the pharmacokinetics (PK) of RGM. Of the 11 drugs that are likely to be co-administered with RGM in diabetic patients, seven drugs lowered the IC 50 value of RGM on CYP2C8 by more than 80%. In vitro CYP2C8 inhibitory assays of RGM in combination with drugs of interest showed that the IC50 of RGM was decreased by 98.9% by AC. In a pharmacokinetic study, Sprague-Dawley (SD) rats were orally administered 1 mg/kg of RGM following by single or 10-consecutive daily administrations of 1.5 mg/kg/day of AC. No significant changes in the pharmacokinetic parameters of RGM were observed after a single administration of AC, but the AUC and Cmax values of RGM were significantly reduced by 36% and 31%, respectively, by multiple administrations of AC. In conclusion, RGM was found to be affected by AC by in vitro CYP2C8 inhibition testing, and multiple dosing of AC appreciably changed the pharmacokinetics of RGM. These findings suggest that a drug interaction exists between AC and RGM.

Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo

“…During sI/R, 0.3 µM rosiglitazone even increased cell survival. The applied dose range of 0.1 to 10 µM corresponds to the human peak plasma concentration range of 0.8 to 1.96 µM (averaged data from humans [32][33][34][35][36][37][38][39][40][41]) and our in vivo peak plasma concentration of approximately 8.2 µM [42,43]. Our results are consistent with data obtained from isolated mitochondria from ARCMs showing no change in reactive oxygen species or membrane potential due to 10 to 50 µM concentrations of rosiglitazone [48].…”

“…In addition, all experiments with chronic rosiglitazone treatment in rats used high doses, which resulted in peak plasma concentrations [30,31] exceeding those in humans [32][33][34][35][36][37][38][39][40][41]. The average peak plasma concentration of rosiglitazone resulting from single-dose administration of 1 mg/kg in rats is greater than the peak plasma concentration in humans after single-dose administration of 4 or 8 mg doses [42,43]. Our dose of 0.8 mg/kg/day more accurately resembles the actual human conditions than those used in other chronic rosiglitazone treatment studies.…”