Inosine monophosphate dehydrogenase expression and activity are significantly lower in kidney transplant recipients with diabetes mellitus

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Background: Inosine 50-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressive drug, mycophenolic acid (MPA). A 12-hour clinical pharmacokinetic and pharmacodynamic study was conducted to compare IMPDH1 and IMPDH2 gene expression, IMPDHI and IMPDHII protein levels, and enzyme activity between kidney transplant recipients with respect to diabetes status. Methods: Nondiabetic (ND, n = 11) and diabetic (D, n = 9) kidney transplant recipients and on nontransplant nondiabetic (n = 10) and diabetic (n = 10) volunteers were included in the study. Results: Area under the effect curve values for gene expression: IMPDH1 [ND: 22.1 (13.8-31.3) versus D: 4.5 (2.3-6.5), P>0.001] and IMPDH2 [ND: 15.3 (11.0-21.7) versus D: 6.1 (4.6-8.6), P> 0.001], protein level: IMPDHI [ND: 1.0 (0.5-1.3) versus 0.5 (0.4- 0.7), P = 0.002] and IMPDHII [ND: 1.0 (0.6-1.6) versus D: 0.7 (0.6-0.8) P>0.001] and enzyme activity [ND: 180 (105-245) versus D: 29.9 (15.3-35.6) mmole$s21$mole21 adenosine monophosphate, P>0.001] was significantly lower in transplant recipients with diabetes. Similar results were observed in nontransplanted volunteers. Kinetic studies of MPA-mediated suppression of IMPDH activity in nontransplanted individuals revealed an approximately 2.5-fold lower half-maximum effective concentration (EC50) for diabetic as compared with nondiabetic [ND: 50.2 (49.8-50.7) versus D: 15.8 (15.6-16.3) nmole/L, P = 0.004] volunteers. This difference was not related to several IMPDH gene variants. Conclusions: This study indicates a significantly lower IMPDH gene expression, protein level, and enzyme activity in diabetic patients. Further clinical studies in a larger number of patients are warranted to verify whether MPA dosing must be optimized for kidney transplant recipients with diabetes mellitus. © 2013 by Lippincott Williams and Wilkins.

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Therapeutic Drug Monitoring