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.

Monitoring of inosine monophosphate dehydrogenase activity and expression during the early period of mycophenolate mofetil therapy in de novo renal transplant patients

Pisani, Francesco;
2013-01-01

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11697/126707
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