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Purpose: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. Methods: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1--2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone ± azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. Results: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p 0.05). One-year patient survival was 93 and 100%, respectively (p > 0.05). Conclusions: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year. more...

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels. more...

P-glycoprotein (P-gp) is involved in the transport of the xenobiotic immunosuppressive agents and many cytokines, such as IL-2 and IFN-gamma. Hence, P-gp activity on peripheral blood lymphocytes (PBLs) could affect the pharmacologic response to xenobiotic immunosuppressants and immune responsiveness. The objectives of this study were to (1) determine the level of P-gp expression and activity on PBLs of kidney transplant candidates; and (2) determine whether P-gp expression correlates with P-gp activity.We measured P-gp expression and activity on CD3(+)/CD8(+), CD3(+)/CD4(+), B lymphocytes, and NK cells of 36 kidney transplant candidates using a flow cytometric assay. P-gp activity was determined for each subpopulation of cells by the ratio of the mean Rhodamine 123 fluorescence (MFI Rh123) in the presence of verapamil divided by the MFI Rh123 in the absence of verapamil. P-gp expression was noted as the percentage of P-gp(+) cells.NK cells exhibited the greatest amount of P-gp activity (MFI Rh123 = 20.2 +/- 16.4) compared with other cell populations (P.05). P-gp efflux activity was also significantly elevated in CD3(+)/CD8(+) cells (13.9 +/- 10.5) compared with B lymphocytes (4.9 +/- 2.7; P.05) and CD4/CD3(+) cells (2.4 +/- 1.0; P.05). P-gp expression was significantly higher in B lymphocytes (11.7 +/- 9.5) and NK cells (10.2 +/- 7.3) when compared with CD3(+)/CD8(+) cells (7.3 +/- 6.9) and CD3(+)/CD4(+) cells (6.4 +/- 3.8). P-gp expression was highly variable and did not correlate with P-gp activity (P.05).CD3(+)/CD8(+) cells and NK cells, exhibited significantly increased P-gp activity compared with the other cell populations. P-gp expression is not a good correlate of P-gp activity. These findings may have important implications for the use of immunosuppressive drugs posttransplant and immune responsiveness after transplantation. more...