Effect of mycophenolate mofetil therapy on inosine monophosphate dehydrogenase induction in red blood cells of heart transplant recipients

Background: Mycophenolic acid is reported to provide effective immunosuppre ssion by inhibiting inosine monophosphate dehydrogenase. In an attempt to m onitor the biological effects of long-term therapy with mycophenolate mofet il, we measured levels of guanosine 5' triphosphate and adenosine 5' tripho sphate in red blood cells (RBCs) of patients after heart transplantations. Methods: Fifty-two patients enrolled in the study were randomly assigned to one of two groups. Patients in the control group (n = 27) received cyclosp orine A (INN, ciclosporin), azathioprine, and prednisone. Patients in the s tudy group (n = 25) were switched from azathioprine to mycophenolate mofeti l 3 months after the heart transplantation. Adenosine 5' triphosphate and g uanosine 5' triphosphate levels were determined by means of HPLC. The activ ities of inosine monophosphate dehydrogenase and hypoxanthineguanine phosph oribosyltransferase, which are responsible for guanine nucleotide fomation, were measured in RBCs by radiochemical methods. Results: Adenosine 5' triphosphate levels were unchanged in patients treate d with mycophenolate mofetil, whereas those of the control group who receiv ed azathioprine (from 142 +/- 26 pmol/10(6) RBCs to 165 +/- 25 pmol/10(6) R BCs; P < .001) increased. As the length of myrophenolate mofetil therapy in creased, patients in the study group showed significantly elevated guanosin e 5' triphosphate levels (15.6 <plus/minus> 6.1 pmol/10(6) RBCs versus 6.6 +/- 2.1 pmol/10(6) RBCs; P < .001) and a 5-fold increase in inosine monopho sphate dehydrogenase activity (108.6 <plus/minus> 13.3 pmol/mg of protein p er hour versus 22.5 +/- 1.7 pmol/mg of protein per hour; P < .001) compared with the control group. In addition, a slight but significant enhancement of hypoxanthine-guanine phosphoribosyltransferase activity was seen in the mycophenolate mofetil group. Conclusions: Our studies have shown that long-term administration of mycoph enolate mofetil is associated with increasing guanosine 5' triphosphate lev els in RBCs as the result of an induction of inosine monophosphate dehydrog enase and hypoxanthine-guanine phosphoribosyltransferase activities in eryt hrocytes.