Human plasma concentration-time profiles of troglitazone and troglitazone sulfate simulated by in vivo experiments with chimeric mice with humanized livers and semi-physiological pharmacokinetic modeling

Abstract

Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Metabolic formation ratio was estimated by comparing AUCs of troglitazone sulfate after separate administration of troglitazone and troglitazone sulfate. Liver to plasma concentration ratios were obtained from direct measurement. These parameters were extrapolated to 100% chimeric mice and subjected to semi-physiological pharmacokinetic modeling using pharmacokinetic parameters for oral administration taken from literature. Our simulated plasma concentration-time profile of troglitazone agreed well with observed values obtained in clinical study. However, the profile of troglitazone sulfate was far below the reported values. Although the possible reasons for this discrepancy remains unsolved, the combination of chimeric mice with semi-physiological PK modeling proved to be a useful tool in understanding the function of each PK parameter in human pharmacokinetics of troglitazone and its conjugated metabolite.

Keywords: Humanized chimeric mouse; Pharmacokinetic modeling; Prediction; Troglitazone; Troglitazone sulfate.