Mycophenolate mofetil administration

Bravo, Y., Quiroz, Y., Ferrebuz, A., Vaziri, N.D., Rodriguez-lturbe, B., 2007. Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension. Am. J. Physiol. Renal Hiysiol. 293, F616—F623. 

Tablets, delayed-release Mycophenolic acid delayed-release tablets and mycophenolate mofetil tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following the administration of these 2 products is not equivalent.

Mycophenolate mofetil (CdlCept), in conjunction with cyclosporine and corticosteroids, has clinical applications in the prevention of organ rejection in patients receiving allogeneic renal and cardiac transplants. By effectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, metabolized in the liver first to the active compound my-cophenolic acid, and then further metabolized to an inactive glucuronide. 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

Mycophenolic acid (MPA) was isolated from cultures of Penicillium spp. in 1896 and was purified in 1913. Initially the compound was studied for its antifungal and antibacterial effects and later for its antitumor effects. Many years later, its immunosuppressive activities were recognized and after further developmental work, an ester prodrug mycophenolate mofetil was developed, which was approved by the United States Food and Drug Administration for the prevention of acute renal allograft rejection in 1995 and for heart transplant recipients in 1998. Mycophenolate mofetil is a cytotoxic agent now used for immunosuppressive therapy and is the mofetil ester of MPA, which is the active immunosuppressive agent. 

Mycophenolate mofetil is rapidly absorbed after oral administration, and the bioavailability of its oral dose is 94%. It is metabolized by esterases to free MPA, which is the active metabolite. The enterohepatic recirculation plays a crucial role in the serum levels of MPA. The active metabolite is further metabolized by glucuronyl transferase and is eliminated (90%) in urine as the MPA glucuronide (MPAG) as a result of the organic anion transport system in the proximal tubule. A small amount is excreted in feces. 

Disposition and Pharmacokinetics Mycophenolate mofetil is rapidly and completely metabolized to MPA after oral or intravenous administration. MPA, in turn, is metabolized to the inactive glucuronide MPAG. The parent drug is cleared from the blood within a few minutes. The tj of MPA is 16 hours. Negligible (<1%) amounts of MPA are excreted in the urine. Most (87%) is excreted in the urine as MPAG. Plasma concentrations of MPA and MPAG are increased in patients with renal insufficiency. In early renal transplant patients (<40 days post-transplant), plasma concentrations of MPA after a single dose of mycophenolate mofetil are approximately half of those found in healthy volunteers or stable renal transplant patients. 

Gimenez F, Foeillet E, Bourdon O, Weller S, Garret C, Bidault R, Singlas E. Evaluation of pharmacokinetic interactions after oral administration of mycophenolate mofetil and valaciclovir or aciclovir to healftiy subjects. Clin Pharmacokinet (2004) 43, 685-92. 

Colestyramine 4 g three times daily for 4 days reduced the AUC of mycophenolic acid by 40% in a group of healthy subjects after they took a single 1.5-g oral dose of mycophenolate mofetil. The UK manufacturers advise caution with concurrent use, while the US manufacturers say that this combination is not recommended. Separating the administration of... 

Mudge DW, Atcheson B, Taylor PJ, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, Nicol DL, Julians PI, Johnson DW. The effect of oral iron administration on mycophenolate mofetil absorption in renal transplant recipients a random ized, controlled trial. Transplanta-tion (2004) 77, 206-9. 

Morrissey P, Gohh R, Madras P, et al. Pulmonary fibrosis secondary to administration of mycophenolate mofetil. Transplantation 1998 65 1414. 

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