Sometimes, drugs and their metabolites in plasma may convert to each other. This phenomenon is called interconversion, which may result in the instability problem of the plasma samples. The instability problem caused by interconversion of the co-existing metabolites may often be ignored, since there is no drug metabolite in the quality control samples prepared for method validation. Pitavastatin lactone (Pi-LAC), a main metabolite of pitavastatin (Pi), is very unstable and easily converted to Pi in plasma. In this paper, simple and rapid LC-ESI-MS/MS methods were developed for the simultaneous determination of Pi and Pi-LAC in human plasma and urine. The sample stability was examined under different conditions. The interconversion of Pi and Pi-LAC was prevented by adding a pH 4.2 buffer solution to the freshly collected plasma samples. Detection was performed using an electrospray ionization (ESI) operating in positive ion multiple reaction monitoring mode by monitoring the ion transitions from m/z 422.2→290.3 (Pi), 404.2→290.3 (Pi-LAC) and m/z 611.3→423.2 (candesartan cilextetil, the internal standard), respectively. The calibration curve of Pi and Pi-LAC in both human plasma and urine showed good linearity over the concentration range of 0.1-200 ng/mL. The established methods were successfully applied to a pharmacokinetic study of pitavastatin calcium tablets in healthy Chinese volunteers after oral administration of 1, 2 and 4 mg single and multiple doses of pitavastatin calcium. The pharmacokinetic parameters of Pi and Pi-LAC in Chinese volunteers were given respectively. The urinary excretion profiles of Pi and Pi-LAC in Chinese volunteers were also presented. After receiving a single 4 mg oral dose of pitavastatin calcium, the average cumulative urinary excretion percentages of Pi and Pi-LAC in Chinese volunteers were (0.41 ± 0.16)% and (6.1 ± 5.0)%, respectively.
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