Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients.
Measurement of inosine-monophosphate dehydrogenase (IMPDH) activity or gene expression was used as a further approach in pharmacokinetics (PK)/pharmacodynamic (PD)-guided mycophenolate mofetil (MMF) therapy. Forty-four de novo kidney transplant patients were enrolled; 35 of these completed the study, and were followed for 24 weeks for clinical status, PK parameters, IMPDH activity and IMPDH1/2 gene expression. IMPDH activity and expression were measured in peripheral blood mononuclear cells before transplant and at week 2,4,12 and 24, drawn before (t0) and 2 h (t2 h) after MMF administration. No significant correlation was found between IMPDH activity/expression and PK parameters. For both genes, significant enhancement in t2 h expression was observed, then decreases towards week 24 with a trend following steroid dosages. Seven patients experienced acute rejection (AR) and exhibited significantly higher pre-transplant expression of both IMPDH1 (median 3.42 vs. 0.84; p=0.0025), and IMPDH2 genes (135 vs. 104; p=0.0218) with respect to non-rejecting patients. A significant association was also found between pre-transplant IMPDH1 mRNA and haematological complications (p=0.032). This study suggests that high steroid dosages may influence IMPDH1/2 expression, hampering their use as a PD biomarker, particularly during the early post-transplant period. The measurement of pre-transplant levels of IMPDH1/2 may contribute to prediction of individual drug responsiveness to improve the clinical management of patients in MMF therapy.
Clinical Pharmacokinetics in Transplantation and Autoimmune Diseases, Foundation IRCCS Policlinico S. Matteo, Pavia, Italy. m.molinaro@smatteo.pv.it
Mariadelfina
M
Molinaro
Laurent R
LR
Chiarelli
Luigi
L
Biancone
Marco
M
Castagneto
Luigi
L
Boschiero
Francesco
F
Pisani
Massimo
M
Sabbatini
Silvio
S
Sandrini
Eloisa
E
Arbustini
Carmine
C
Tinelli
Mario
M
Regazzi
Francesco P
FP
Schena
Giuseppe P
GP
Segoloni
D000328:Adult; D015415:Biomarkers; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006084:Graft Rejection / Q000235:genetics; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D015415:Biomarkers; D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid