Effect of Diabetes Mellitus on Mycophenolate Sodium Pharmacokinetics and Inosine Monophosphate Dehydrogenase Activity in Stable Kidney Transplant Recipients

Abstract

Effect of diabetes mellitus on mycophenolic acid (MPA) pharmacokinetics and catalytic activity of inosine monophosphate dehydrogenase (IMPDH) was investigated in maintenance kidney transplant recipients. Demographically matched diabetic (n=9) and nondiabetic (n=9) patients were included in a 12-hour open-label, steady-state study after oral administration of enteric-coated mycophenolate sodium. Concentrations of total MPA and free MPA, MPA-glucuronide, and acyl-MPA-glucuronide were measured and oral acetaminophen absorption was used as a marker for gastric-emptying rate. Median (range) of MPA area under the curve(0-12) was 36.7 (range, 16.4-116.4) mg*h/L in diabetic and 48.2 (range, 34.9-80.1) mg*h/L in nondiabetic patients (P=0.49). All other primary pharmacokinetic parameters, including time to maximum concentration, for total or unbound MPA as well as MPA metabolites were comparable. In contrast, IMPDH activity was 17.5+/-2.8 versus 46.6+/-2.5 nmol XMP/h/microg protein in diabetics and nondiabetics, respectively (P<0.0001) and was significantly lower in the diabetics irrespective of concomitant therapy with cyclosporine or tacrolimus. This study demonstrated that diabetes does not alter MPA pharmacokinetics when administered as enteric-coated mycophenolate sodium; however, IMPDH activity appeared to be significantly lower in patients with diabetes independent of the unbound or total concentrations of MPA. Further investigations are warranted to investigate the regulation of IMPDH enzyme in patients with diabetes.