Pharmacokinetics of TAK‐875 and its toxic metabolite TAK‐875‐ acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry

TAK‐875 is a selective partial agonist of human GPR40 receptor, which was unexpectedly terminated at phase III clinical trials owing to its severe hepatotoxicity. The purpose of this study was to investigate the pharmacokinetics of TAK‐875 and its toxic metabolite TAK‐875‐acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry (LC–MS/MS). Plasma samples were extracted with ethyl acetate and chromatographic separations were achieved on a C₁₈ column with water and acetonitrile containing 0.05% ammonium hydroxide as mobile phase. The sample was detected in selected reaction monitoring mode with precursor‐to‐product ion transitions being m/z 523.2 → 148.1, m/z 699.3 → 113.1 and m/z 425.2 → 113.1 for TAK‐875, TAK‐875‐acylglucuronide and IS, respectively. The assay showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 0.5 ng/mL for both analytes. The extraction recovery was >78.45% and no obvious matrix effect was detected. The highly sensitive LC–MS/MS method has been further applied for the pharmacokinetic study of TAK‐875 and its toxic metabolite TAK‐875‐acylglucuronide in rat plasma. Pharmacokinetics results revealed that oral bioavailability of TAK‐875 was 86.85%. The in vivo exposures of TAK‐875‐acylglucuronide in terms of AUC_0–t were 17.54 and 22.29% of that of TAK‐875 after intravenous and oral administration, respectively.