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An immunosuppressive antimetabolite, mycophenolate mofetil (MMF), has been widely used in combination with a calcineurin inhibitor for organ transplantation and autoimmune diseases. A fixed dosing of MMF often causes bone marrow toxicity or cytomegalovirus antigenemia under the optimal dosing of calcineurin inhibitors. Pharmacokinetic characteristics of MMF and its relation to the degree of immune suppression have not been fully clarified in clinical practice. This review summarizes our achievements on pharmacokinetic disposition of mycophenolic acid (MPA) and inosine 5'-monophosphate dehydrogenase (IMPDH) activity in patients with kidney transplantation and with lupus nephritis. Contribution of enterohepatic recirculation to plasma disposition of MPA in lupus nephritis patients was similar to that in tacrolimus-treated kidney transplant recipients. MPA pharmacokinetics in lupus nephritis was characterized by high MPA clearance most likely due to better renal function. In addition, concomitant metal cation decreased MPA concentration in patients receiving tacrolimus but not cyclosporine. This interaction may depend on amount of biliary-excreted MPA glucuronide. Renal clearance of MPA was higher in cyclosporine- than tacrolimus-treated patients. Its ratio to creatinine clearance was much higher than unbound fraction of MPA in each calcineurin inhibitor treatment. These kinetic data revealed the presence of renal tubular secretion in the urinary excretion process. In multivariate analysis, the plasma disposition of MPA and its glucuronides affected IMPDH activity in erythrocytes. The IMPDH activity might be a useful marker reflecting a long-term exposure by MPA. Our findings in this review would contribute to optimal dosing of MMF in immunosuppressive regimen including a calcineurin inhibitor.

Recently, many immunosuppressants have been developed and some of them have already been introduced in clinical organ transplantation. With a new concept of immunoregulation, which focuses on prevention of rejection and over-immunosuppression, the latest protocol has been conducted. Chimeric or humanized antibodies targeting the lymphocyte surface molecule such as CD19, 20, 25, 40, and 52 are administrated in the induction phase, and calcineurin inhibitors (cyclosporin and tacrolimus) are used as key drugs. For tapering the doses of them, the combined application of anti-metabolic agents of azathioprine, mizoribine, or mycophenolate mofetil (MMF) has been proved effective. Lymphocyte forming drugs induce unique immunoregulation, targeting at sphingosine 1-phosphate (SlP) receptors. FTY720 is now in the procedure of clinical trial to compare with MMF. KRP203 is also a candidate for more specific SIP receptor agonist. In this issue, I reviewed the recent immunosuppressive strategy and focused on the advance of novel immunosuppressive drugs.

Allopurinol is used frequently to treat patients with gout and hyperuricemia. However, adverse effects associated with this agent have been reported occasionally, especially among patients with hyperuricemia complicated with renal diseases. A rise in the blood concentration of oxipurinol, the chief active metabolite of allopurinol, has been noted in patients with renal dysfunctions, pointing to an implication of oxipurinol toxicity. It has been reported that monitoring the serum oxipurinol concentration to maintain in level below 15.2 micrograms/ml (= 100 mumol/l: recommended level) is helpful in avoiding toxicity. At Jikei University Hospital, a survey was conducted on 148 hyperuricemic patients who had been treated with allopurinol at the dosages of 50, 100, 200 and 300 mg daily or 100 mg on alternate days for more than one month. Because oxipurinol is an uricosuric substance, the steady-state serum oxipurinol concentration was determined by HPLC; and creatinine clearance (CCr) was calculated for each patient. 1. In the group composed of patients with normal kidney function (CCr > or = 80 ml/min), increase in the dosage of allopurinol was associated with a linear increase in the serum concentration of oxipurinol. 2. Among the patients with varying renal function who were receiving 100 mg of allopurinol daily, the oxipurinol level increased logarithmically as the creatinine clearance decreased. In some of the patients with renal insufficiency (CCr < 30 ml/min), daily administration of 100 mg of allopurinol resulted in a serum concentration of oxipurinol over 15.2 micrograms/ml. 3. For patients with renal insufficiency (CCr < 30 ml/min), administration of allopurinol at the dosage of 50 mg/day is considered adequate to avoid the accumulation of serum oxipurinol.