title: Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution.
abstract: Endoplasmic reticulum (ER) stress is associated with various human diseases. Phenylbutyric acid (PBA) is a well-known chemical chaperone that regulates ER stress. The main objective of this study was to develop a simple, rapid, and sensitive method for the simultaneous determination of phenylbutyric acid and its metabolite, phenylacetic acid (PAA). A LC-MS/MS analysis using negative electrospray ionization was used. Samples were analyzed by multiple reaction monitoring (MRM) in 15 min of total run time, using d11-PBA and d7-PAA as internal standards. The limit of quantification was 1 μg/g for tissue and 0.8 μg/mL for plasma. Recoveries for plasma and tissues were higher than 81% for both PBA and PAA. The inter-day and intra-day accuracy and precision were within ±15%. We then further successfully validated this method by applying it to determine the tissue distribution of PBA and its metabolite PAA after i.p. injection of PBA at a dose of 500 mg/kg in mice. The maximum concentrations of PBA and PAA in plasma and tissues were seen at 15 min and 45 min, respectively. The PBA plasma concentration was 15-fold higher than the concentration in the kidney, whereas the PAA plasma concentration was 6-fold higher than the concentration in the liver. The area under the curve decreased in the order of plasma > kidney > liver > heart > muscle > lung for PBA and plasma > liver > kidney > heart > muscle > lung for PAA. The tissue to plasma ratio ranged from 0.007 to 0.063 for PBA and 0.016 to 0.109 for PAA. In summary, the LC-ESI-MS method developed in this study is simple, sensitive and reliable.
authors: Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju 560-182, South Korea.
authors: Anu
authors: A
authors: Marahatta
authors: Bidur
authors: B
authors: Bhandary
authors: Mi-Rin
authors: MR
authors: Lee
authors: Do-Sung
authors: DS
authors: Kim
authors: Yong Chul
authors: YC
authors: Lee
authors: So-Ri
authors: SR
authors: Kim
authors: Hyung-Ryong
authors: HR
authors: Kim
authors: Han-Jung
authors: HJ
authors: Chae
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D016018:Least-Squares Analysis; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010648:Phenylacetates / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D010654:Phenylbutyrates / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D010648:Phenylacetates; D010654:Phenylbutyrates; C025136:phenylacetic acid