Concise synthesis of the major metabolite M8 from ticagrelor and simultaneous determination of ticagrelor and M8 by a novel LC/MS method

Ticagrelor is an oral antiplatelet agent that has been approved for preventing de novo and recurrent acute coronary syndrome. To date, only a few studies have attempted to clarify population differences in the pharmacokinetics and pharmacodynamics of ticagrelor between Caucasians and Asians. Our aim was to develop a simple quantification method for ticagrelor and its pharmacologically active metabolite M8 (AR-C124910XX) in human plasma and urine. First, we concisely synthesized M8 from ticagrelor via a five-step sequence: the hydroxyethyl group of ticagrelor was removed by bromination and subsequent zinc-mediated chemoselective reduction. Then, we developed a simple liquid chromatography–mass spectrometry method using ticlopidine as an internal standard. Ticagrelor, M8, and internal standard were separated with a reverse-phase C 18 column, and ticagrelor and M8 were detected at m/ z [+] of 523.25 and 479.25, respectively, with good sensitivity and precision in the concentration ranges of 10 to 100 µM and 5 to 50 µM, respectively. This novel liquid chromatography–mass spectrometry system may be attractive to investigators in private laboratories because it is less costly than liquid chromatography/mass spectrometry/mass spectrometry systems. Our method is expected to accelerate further clinical studies on the disposition and pharmacodynamics of ticagrelor.