Expression of IMPDH1 is regulated in response to mycophenolate concentration.
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes de novo guanine nucleotide synthesis. Mycophenolic acid (MPA) exerts immunosuppressive effects by inhibiting IMPDH. The aim of this study was to investigate gene expressions of two IMPDH isoforms, during in vivo exposure to MPA. Healthy volunteers (n=5) were given single doses of 100, 250, 500 and 1000 mg mycophenolate mofetil (MMF). Blood was sampled pre-dose and at 1, 2, 4, 6, 8, 12, and 24 h post-dose. The expressions of IMPDH 1 and 2 were quantified in CD4+ cells and whole blood by real-time reverse transcription-PCR. Following MMF doses of 500 mg, the expression of IMPDH 1 and 2 in CD4+ cells was reduced 39% (P=0.043) and 10% (P=0.043), respectively. Smaller reductions (ns) were observed after 1000 mg MMF. Similar trends were demonstrated for whole blood. The largest reductions of IMPDH1 occurred at MPA AUC(0-12 h) of 20 mg h/L. Below this, increasing MPA exposure correlated with larger reductions of IMPDH1 expression (CD4+ cells: r=-0.82, P<0.001, and whole blood: r=-0.50, P=0.04, n=17), while higher MPA exposure seemed to be associated with smaller reductions of expression (CD4+ cells: r=0.42, ns, and whole blood: r=0.77, P=0.039, n=8). The concentration-dependent modulation of IMPDH 1 and 2 expressions by MPA might impact IMPDH activity. Knowledge of the regulation of the two IMPDH isoenzymes in vivo by MPA is of importance considering pharmacodynamic monitoring and optimization of MPA treatment.
Bremer
Sara
S
Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway.
Vethe
Nils T
NT
Rootwelt
Helge
H
Bergan
Stein
S
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D018592:Cross-Over Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D020033:Protein Isoforms; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D009173:Mycophenolic Acid