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Abstract
A sensitive, reliable and specific LC-MS-MS method was developed and validated for the identification and quantitation of all-trans retinoic acid (ATRA) in human plasma. Acitretin was used as the internal standard (IS). After liquid-liquid extraction of 500 μL plasma with methyl tert-butyl ether (MTBE), ATRA and the IS were chromatographed on a HyPURITY C18 column (150 mm × 2.1 mm, 5 μm) with the column temperature set at 40 °C. The mobile phase was consisted of 40% phase A (MTBE–methanol–acetic acid, 50:50:0.5, v/v) and 60% phase B (water–methanol–acetic acid, 50:50:0.5, v/v) with a flow rate of 0.3 mL/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) mode via the positive electrospray ionization interface using the transition m/z 301.4 → 123.1 for ATRA and m/z 326.9 → 177.1 for IS, respectively. The calibration curve was linear over the range of 0.45–217.00 ng/mL (r ≥ 0.999) with a lower limit of quantitation (LLOQ) of 0.45 ng/mL. The intra- and inter-day precisions values were below 8% relative standard deviation and the accuracy was from 98.98% to 106.19% in terms of relative error. The validated method was successfully applied in a bioequivalence study of ATRA in Chinese healthy volunteers.
Highlights
Acute promyelocytic leukemia (APL), classified as acute myeloid leukemia (AML) subtype M3 is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARα or RARA) gene, which is distinct from other forms of AML in its responsiveness to all-trans retinoic acid (ATRA) therapy
(10:20:1, v/v/v) were all investigated as extraction solvents, and methyl tert-butyl ether (MTBE) was employed because of its higher extraction recovery (>75%) to ATRA and internal standard (IS)
Samples were isolated by Liquid-liquid extraction (LLE), separated on a C18 column and quantified by liquid chromatography-mass spectrometry (LC-MS)-MS
Summary
Acute promyelocytic leukemia (APL), classified as acute myeloid leukemia (AML) subtype M3 is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARα or RARA) gene, which is distinct from other forms of AML in its responsiveness to all-trans retinoic acid (ATRA) therapy. As an analogue of vitamin A, ATRA is able to induce apoptosis and differentiation of immature promyelocytes and decrease the risk of bleeding in patients with APL [2]. In addition to its pharmacodynamics, the pharmacokinetics of ATRA plays a significant role for its efficacy in the treatment of APL. Continued oral doses of ATRA were associated with a significant decrease in both the area under the concentration-time curve and the plasma peak levels (p = 0.004 and 0.01, respectively) when tested after 2–6 weeks of treatment [3]. No accumulation was observed after multiple doses and ATRA was not retained in tissues.
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