Sensitive and validated LC-MS/MS methods to evaluate mycophenolic acid pharmacokinetics and pharmacodynamics in hematopoietic stem cell transplant patients

Misaki Kawanishi, Ikuko Yano, Kazuaki Yoshimura, Takashi Yamamoto, Sachiyo Hashi, Satohiro Masuda, Tadakazu Kondo, Akifumi Takaori-Kondo, Kazuo Matsubara

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20 Citations (Scopus)

Abstract

Monitoring of pharmacodynamics in addition to pharmacokinetics is one of strategies to individualize mycophenolate mofetil therapy. The purpose of this study was to develop sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for evaluation of the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA). Concentrations of mycophenolic acid glucuronide (MPAG), mycophenolic acid acyl-glucuronide, as well as unbound MPA and MPAG, were determined, and inosine-5′-monophosphate dehydrogenase activity was calculated by measuring concentrations of produced xanthosine-5′-monophosphate (XMP) and intracellular adenosine-5′-monophosphate after incubation of peripheral blood mononuclear cell (PBMC) lysates. A metal-free MastroTM column and two gradient patterns were used to improve the quantification limit of XMP to 0.1 μm. In the clinical MPA concentration range, the linearity of the calibration curve, inter- and intra-day precision and accuracy satisfied the relevant US Food and Drug Administration guidelines. The MPA concentrations in hematopoietic stem cell transplant (HSCT) patients determined by the enzyme assay and the present LC-MS/MS method showed a good correlation (r2 = 0.95, p < 0.001). In this study, we report sensitive and validated LC-MS/MS methods to evaluate the pharmacokinetics and pharmacodynamics of MPA, which are sufficiently sensitive to assess small quantities of PBMC lysates collected shortly after HSCT.

Original languageEnglish
Pages (from-to)1309-1316
Number of pages8
JournalBiomedical Chromatography
Volume29
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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