Molecular Pharmacodynamics of the Immunosuppressant Mycophenolic Acid: : A Basis for Monitoring and Individualized Treatment
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AbstractThe immunosuppressant mycophenolic acid (MPA) is included in post-transplant rejection prophylaxis regimens. Individualization of the MPA therapy may improve the clinical outcome. The aims of this thesis in pharmacology were to develop methods for the assessment of MPA pharmacodynamics in clinical samples, and to provide in-depth knowledge of the pharmacokinetic-pharmacodynamic characteristics at the molecular level.
MScPharm Nils Tore Vethe and colleagues performed studies in renal transplant patients and healthy individuals, and in cultured cells. The target enzyme inosine monophosphate dehydrogenase (IMPDH) was transiently inhibited by MPA. The effect was immediate and most pronounced during the first half of the 12 hrs dose interval. In whole blood cells from renal transplant patients and in cultured MOLT-4 leukemia cells it was observed that MPA altered the underlying IMPDH activity. An assay for the determination of IMPDH activity in CD4+ cells was developed and validated. This assay was applied to assess the MPA-mediated IMPDH inhibition during a single-dose exposure-response study in healthy individuals. Plasma concentrations of MPA above approximately 6 mg/L did not inhibit the IMPDH activity any further. The overall IMPDH activity approached maximum reduction when the area under the concentration-time curve (0-12 hrs) exceeded 22 mg„eh/L. The results suggest that the standard clinical dosing corresponds to MPA exposure in the upper range of the exposure-response curve. No immediate guanine nucleotide reductions were observed in circulating CD4+ cells in response to MPA.
Future studies are needed to characterize the potential relationship between IMPDH activity and clinical outcome during MPA therapy. Integrated monitoring of IMPDH activity and MPA concentration may help identifying patients who are over- or under-exposed to MPA.
Paper I: Vethe NT, Mandla R, Line PD, Midtvedt K, Hartmann A, Bergan S. Inosine monophosphate dehydrogenase activity in renal allograft recipients during mycophenolate treatment. Scand J Clin Lab Invest. 2006;66(1):31-44
Paper II: Vethe NT, Bergan S. Determination of inosine monophosphate dehydrogenase activity in human CD4+ cells isolated from whole blood during mycophenolic acid therapy. Ther Drug Monit. 2006 Oct;28(5):608-13
Paper III: Vethe NT, Bremer S, Bergan S. IMP dehydrogenase basal activity in MOLT-4 human leukaemia cells is altered by mycophenolic acid and 6-thioguanosine. Scand J Clin Lab Invest. 2008;68(4):277-85
Paper IV: Vethe NT, Bremer S, Rootwelt H, Bergan S. Pharmacodynamics of mycophenolic acid in CD4+ cells: A single-dose study of IMPDH and purine nucleotide responses in healthy individuals. Ther Drug Monit. 2008; Epub ahead of print. Ther Drug Monit. 2008 30(6):647-55