Pharmacokinetics

Mycophenolate mofetil and mycophenolate sodium are rapidly and completely absorbed, and quickly de-esterified in the blood and tissues to MPA, the active form of the drug. The half-life of mycophenolate mofetil during intravenous administration is <2 min (179). Following an oral dose of mycophenolate mofetil, MPA reaches a maximum concentration within 1 h (180). Almost all the drug (>99%) can be found in the plasma compartment (181). For this reason, serum or plasma MPA concentrations are used for routine therapeutic drug monitoring of MPA.

MPA has an elimination half-life of 18 h and is glucuronidated in the liver to the primary inactive metabolite, 7-o-glucuronide mycophenolic acid (MPAG) (182). Small quantities of the inactive metabolite 7-o-glucoside are also produced in the liver (180,183). Another metabolite produced in small quantities is acyl glucuronide, an active metabolite that may contribute to the adverse gastrointestinal effects of MPA (184). MPAG exhibits significant enterohepatic recirculation with a second MPA plasma peak occurring 4-12 h after drug administration. The kidneys primarily clear MPAG with concentrations rapidly accumulating in patients with severe renal impairment (glomerular filtration rates <25 mL/min) (185). MPA is extensively bound in the circulation to albumin with typical concentrations of free or unbound MPA ranging from 1.25 to 2.5% of the total concentration (181). Free MPA concentrations are increased in hypoalbuminemia, hyperbilirubinemia, and uremia (186). It has been shown that the immunosuppressive effects of MPA are related to free MPA and not the total drug concentration (181). In chronic renal failure, the free concentration of MPA can increase dramatically indicating over immunosuppression when the total MPA concentration is within the therapeutic range (186,187).

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