Determination and pharmacokinetics study of UK-5099 in mouse plasma by LC-MS/MS.

Abstract

BACKGROUND: UK-5099 is a potent mitochondrial acetone carrier inhibitor, that exhibits anticancer activity. Recently, the anti-Toxoplasma gondii activity of UK-5099 was proposed, and in vivo studies of its pharmacokinetics in BALB/c mice are necessary to further evaluate the clinical effect of UK-5099. METHODS AND RESULTS: A simple and fast high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis method was established and verified in terms of its linearity, matrix effect, accuracy, precision, recovery and stability. The analytes were separated by an Agilent ZORBAX XDB-C18 column (2.1 × 50 mm, 3.5 μm) at 30 °C. A gradient mobile phase consisting of water with 0.1% formic acid (FA) (phase A) and acetonitrile (ACN) (phase B) was delivered at a flow rate of 0.40 mL·minwith an injection volume of 5 μL. A good linear response was obtained in a concentration range of 5-5000 ng·mL(r = 0.9947). The lower limit of quantification (LLOQ) was 5 ng·mL. The extraction recovery of UK-5099 was greater than 95%. The inter- and intra-day accuracy and precision of the method showed relative standard deviations (RSDs) of less than 15%. This method has been successfully applied to the pharmacokinetic evaluation of UK-5099 in mouse plasma. In health mice, the main pharmacokinetic parameters of UK-5099 after intraperitoneal administration were measured using a noncompartmental model, in which the AUCwas 42,103 ± 12,072 ng·h·mLand the MRTwas 0.857 ± 0.143 h. The peak concentration (C) was 82,500 ± 20,745 ng·h·mL, which occurred at a peak time (T) = 0.250 ± 0.000 h. CONCLUSIONS: A fast and sensitive HPLC-MS/MS method was developed, validated and successfully used for the determination of UK-5099 levels in mice after intraperitoneal administration. This study was the first report of the pharmacokinetic parameters of UK-5099 in mice, which will help to further study the administration of UK-5099 in animals and humans.