Abstract
Acetyl triethyl citrate (ATEC) is a water-soluble plasticizer used in pharmaceutical plasticized polymers. In this study, the pharmacokinetics and metabolism of ATEC were investigated using liquid chromatography–tandem mass spectrometry (LC–MS/MS) in rats. Plasma protein precipitation with methanol was used for sample preparation. For chromatographic separation, a C18 column was used. The mobile phases consisted of 0.1% formic acid and 90% acetonitrile, and gradient elution was used. The following precursor-product ion pairs were selected for reaction monitoring analysis: 319.1 m/z → 157 m/z for ATEC and 361.2 m/z → 185.1 m/z for tributyl citrate (internal standard) in positive ion mode. The LC–MS/MS method was fully validated and successfully applied to a pharmacokinetic study of ATEC in rats. The pharmacokinetic study showed that the volume of distribution and mean residence time of ATEC were higher after oral administration than after intravenous administration, pointing to extensive first-pass metabolism and distribution in tissue. In addition, the plasma concentration profile of the postulated metabolites of ATEC was investigated in plasma, urine, and feces. The resulting data indicated that ATEC was extensively metabolized and excreted mainly as metabolites rather than as the parent form. The developed analytical method and the data on the pharmacokinetics and metabolism of ATEC may be useful for understanding the safety and toxicity of ATEC.
Highlights
Plasticized polymers are substantial in pharmaceutical technology
Acetyl triethyl citrate (ATEC) is used as a hydrophilic plasticizer in the coating of press-coated tablets that are composed of hydroxypropyl methylcellulose acetate succinate or enteric polymer films consisting of polymethacrylic acid methylmethacrylate [1,2,3,4,5]
In the developmental toxicity test with Xenopus laevis embryos, the 96 h EC50 for malformation of ATEC was 413.8 mg/L, and the 96 h lowest observed effective concentration for malformation of embryos was 363.5 mg/L [8]. These results indicate that the teratogenic potential of ATEC would be negligible, and its developmental toxicity may be quite low
Summary
Plasticized polymers are substantial in pharmaceutical technology. For example, they can be used as coating materials of dosage forms, free membranes of pharmaceutical films, polymeric membranes of transdermal system, matrix systems for extended release formulations, or microparticles [1]. Acetyl triethyl citrate (ATEC) is one of the plasticizers used in pharmaceutical plasticized polymers [1]. It is an aliphatic ester of citric acid which is a clear oily liquid with essentially no odor. The same study reported no adverse effects of ATEC on blood cells [6]. In the developmental toxicity test with Xenopus laevis embryos, the 96 h EC50 for malformation of ATEC was 413.8 mg/L, and the 96 h lowest observed effective concentration for malformation of embryos was 363.5 mg/L [8]. Another study indicated that ATEC has no effects on estrogen or antiestrogen activity or steroidogenesis. No studies have reported the use of liquid chromatography–tandem mass spectrometry (LC–MS/MS) for ATEC analysis. On the basis of the developed method, we investigated the pharmacokinetic properties of ATEC in rats
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