Appendix L. 
357 
as primary immunosuppressive therapy. Unlike CyA, hirsuitism and 
gingival hyperplasia occur infrequently with tacrolimus; thus, 
tacrolimus-based therapy may improve compliance and quality of life 
in female and pediatric transplant recipients. It should be noted that 
alopecia has been documented with tacrolimus, but is known to 
improve with dose reductions. The decreased incidence of 
hypertension and hyperlipidemia with tacrolimus makes it preferable 
to CyA in patients with difficult to treat hypertension or 
hyperlipidemia. A final indication for tacrolimus has been as a rescue 
immunosuppressant in cardiac transplant recipients on CyA with 
refractory rejection or intolerance to immunosuppression (severe side 
effects). Since tacrolimus is metabolized using the same cytochrome 
P450 enzyme system as CyA, drug interactions are essentially the 
same. Thus, drugs that induce this system may increase the 
metabolism of tacrolimus, thereby decreasing its blood levels. 
Conversely, drugs that inhibit the P450 system decrease the 
metabolism of tacrolimus, thereby increasing its blood levels. It is 
important to note that some studies have indicated a higher 
incidence of nephrotoxicity v\rith tacrolimus as compared to CyA. 
Azathioprine and Mycophenolate Mofetil (MMF) 
Despite being available for more than 35 years, azathioprine is still a 
useful agent as an immunosuppressive agent. Following 
administration, azathioprine is converted into 6-mercaptopurine, 
with subsequent transformation to a series of intracellularly active 
metabolites. These inhibit both an early step in de novo purine 
synthesis and several steps in the purine salvage pathway. The net 
effect is depletion of cellular purine stores, thus inhibiting DNA and 
RNA synthesis, the impact of which is most marked on actively 
dividing lymphocytes responding to antigenic stimulation. In 
currently used immunosuppressive protocols, azathioprine is used as 
part of a triple therapy regimen along vrith CyA or tacrolimus and 
prednisone. Mycophenolate mofetil (MMF), which is rapidly 
hydrolyzed after ingestion to mycophenolic acid, is a selective, 
noncompetitive, reversible inhibitor of onosine monophosphate 
dehydrogenase, a key enzyme in the de novo synthesis of guanine 
nucleotides. Unlike other marrow-derived cells and parenchymal 
cells that use the hypoxanthine-guanine phosphoribosyl transferase 
(salvage) pathway, activated lymphocytes rely predominantly on the 
de novo pathway for purine synthesis. This functioned selectivity 
allows lymphocyte proliferation to be specifically targeted with less 
anticipated effect on erythropoiesis and neutrophil production than is 
seen with azathioprine. 
PRE -PUBLICATION VERSION 
