Quantitation of mycophenolic acid and metabolites by UPLC-MS/MS in renal transplant patients   全文下載

Quantitation of mycophenolic acid and metabolites by UPLC-MS/MS in renal transplant patients

Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), specific inhibitors of lymphocyte proliferation, are commonly used as adjuvant therapy with calcineurin inhibitor agents after kidney transplantation. After administration, MMF and EC-MPS are hydrolyzed to mycophenolic acid (MPA), the active form of the drug, which must be monitored due to its narrow therapeutic window, drugedrug interactions, and large intra-and inter-individual pharmacokinetic variability despite a fixed dose. Monitoring plasma MPA level is recommended to maintain the drug within the therapeutic window, optimize its efficacy, and minimize side effects. This study aims to develop a method for quantifying MPA and its major metabolites (mycophenolic acid glucuronide [MPAG]) using on-line solid phase extraction (SPE) coupled with an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in kidney transplant patients. The linearity of MPA and MPAG were 0.3e13.6 mg/mL and 2.6e232.9 mg/mL, respectively (r2 > 0.999). The relative error of accuracy was <15%. The within-run and between-run imprecision was <5.8%. No carryover, ion suppression, or ion enhancement were observed. This method was used to analysis of 351 plasma samples from renal transplant patients after MMF or EC-MPS using this method showed large pharmacokinetic variability be-tween patients. Analysis of the same samples by immunoassay showed a large positive bias compared with our vali-dated UPLC-MS/MS method, averaging 15.1%. These results suggest that this UPLC-MS/MS method is more effective than immunoassay for quantitation of MPA and its metabolites in clinical samples.