Development and optimization of a high-throughput high-performance liquid chromatography-tandem mass spectrometric method for the simultaneous determination of naringenin and its valine carbamate prodrug in rat plasma.

A valine carbamate prodrug of naringenin called 4\u0027V was synthesized to enhance its oral bioavailability because of low water solubility and poor membrane permeability of naringenin. Here, a sensitive, rapid, and robust high-performance liquid chromatography-tandem mass spectrometric (HPLC-MS/MS) method was developed and fully validated for the simultaneous determination of naringenin and 4\u0027V in plasma. The analytes were treated with liquid-liquid extraction, and then separated on a Phenomenex Kinetex® XB-C18 column, and detected by a triple-quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) interface. The analytes were eluted within only 4 min by gradient procedure. The excellent linear correlations were validated over the range of 4-400 ng/mL (r = 0.9990) for naringenin and 2-2000 ng/mL (r = 0.9951) for 4\u0027V, with lower limits of quantification of 4 ng/mL and 2 ng/mL, respectively. For all quality control samples, the intra-day and inter-day precision and accuracy were within ± 15%. The validated method was economical, high-throughput, and reliable, and was first successfully applied to a pharmacokinetic study of naringenin and 4\u0027V after oral administration to Sprague-Dawley rats. The results of the pharmacokinetic study demonstrated that the idea of amino acid carbamate prodrug is a promising strategy to improve bioavailability of NAR.