肝移植受者霉酚酸药代动力学与药效学相关性研究-外科学(普外科)专业论文.docxVIP

上海交通大学医学院硕士学位论文 上海交通大学医学院硕士学位论文 CORRELATION BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS OF MYCOPHENOLIC ACID IN LIVER TRANSPLANT RECIPIENTS ABSTRACT Background: Mycophenolic acid (MPA), the active drug moiety of Mycophenolate mofetil (MMF), exerts its immunosuppression by inhibiting inosine monophosphate dehydrogenase (IMPDH), depleting guanine nucleotides of activated lymphocytes and retarding their proliferation. MMF has gained widespread acceptance as the antimetabolite immunosuppressant in organ transplant regimens. In combination with calcineurin and corticosteroid, MMF effectively inhibits acute rejection in solid organ transplant recipients. MPA has a relatively narrow therapeutic window and exhibits wide inter- and intrapatient pharmacokinetic variability, and the fix-dose regimen doesn’t fit all patients. In order to improve efficacy and reduce toxicity, therapeutic drug monitoring was suggested as a strategy to tailor the MPA exposure to each patient’s individual needs. Despite increasing therapeutic drug monitoring use, the benefit of MMF dose adjustments based on target MPA exposure is still controversial. Elucidating the relationship between MPA pharmacodynamics, pharmacokinetics and clinical outcomes may prove an additional and valuable tool in individualizing therapy. Part One: Effects of Mycophenolic Acid on Proliferation of CEM cells in vitro To investigate the relationship between MPA pharmacokinetics and proliferation of CEM cells in vitro. Twenty liver transplant patients received MMF in combination with Tacrolimus. Plasma MPA concentration was determined by enzyme-multiplied immunoassay technique (EMIT) before MMF dose and at 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after dosing. The inhibitory capacity of serum MPA on proliferation of CEM cells was also monitored at 0 h, 1 h and 2 h. The rate of proliferation of CEM cells before MMF administration was higher significantly than those at 1 h and 2 h after dosing (P 0.05). The