Simultaneous determination of BGT-002 and its acyl glucuronide metabolite ZM326E-M2 in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D6-ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D6-ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500-50.0 μg/mL for BGT-002 and 0.0100-10.0 μg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (tmax) of 1.13 h, compared with BGT-002, the tmax (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research.