The Biopharmaceutical Analysis And Preclinical Toxicokinetics Study Of A-Lipoic Acid

ObjectiveOur present work aims to comprehensively evaluate the pre-clinical toxicokinetics of a-Lipoic acid, and compare the differences of toxicokinetics in Beagle dogs and SD rats. And we initially identified the disposition process of the drug in vivo. The results provided a solid basis for the preparation and clinical research of a-Lipoic acid.MethodsIn this paper, we have developed and validated a sensitive and reliable liquid chromatography tandem mass spectrometric method for the determination of a-Lipoic acid in plasma of dog and rat.And the biological samples were pretreated by simple protein precipitation(PP)using acetonitrile, All chromatographic separations were performed using a mobile phase of methnol(A)and water(B) and a XAqua C18column(150mm×4.6mm,5μm) and the mobile phase flow rate was set at 1.0m L/min.All LC methods involved the following set-up:(0min,20%A; 0~2min, 20%A~20%A;2.01~3.00 min,20%A~95%A;3.01~7.00 min,95%A~95%A;7.01~9.00 min,20%A~20%A) Ibuprofen was choosed as IS in the end because of its similarity in retention action, ionization and extraction efficiency. The mass spectrometer was operated in the negative MRM mode with electrospray ion source. Transitions of m/z205.0→171.0 and m/z 205.0-161.0 were used in the MRM experiments to quantitate LA and IS, respectively.ConclusionAccording to pre-clinical research technical guidelines for chemicals, we carried out overall methodological evaluation, the specificity, linearity, accuracy, precision,recovery, matrix effect, dilution effect and stability satisfied the requirements of the guidelines. The method has been successfully applied to the preclinical toxicokinetics studies of a-Lipoic acid. During the experiment,no obvious differences for systemicexposure(AUC) among three dosages were observed between day 1 and day 28,which demonstrated no significant body damage shown after 28 days repeat-dose toxicology studies at three dosages in rat and dog.There are linear features to a-Lipoic in Beagles dog and SD rats.and there is no significant drug accumulation.