[해외논문]Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings원문보기
Zucker, Keith
(Address of correspondence: K. Zucker, Department of Surgery, Division of Transplantation, University of Miami School of Medicine, PO Box 012440 (R-440), Miami, FL 33101, USA.)
,
Rosen, Anne
(Division of Transplantation, Department of Surgury, University of Miami School of Medicine, and The Miami Veterans Administration Medical Center, Miami, Florida U.S.A.)
,
Tsaroucha, Alexandra
(Division of Transplantation, Department of Surgury, University of Miami School of Medicine, and The Miami Veterans Administration Medical Center, Miami, Florida U.S.A.)
,
de Faria, Ludmilla
(Division of Transplantation, Department of Surgury, University of Miami School of Medicine, and The Miami Veterans Administration Medical Center, Miami, Florida U.S.A.)
,
Roth, David
(Division of Transplantation, Department of Medicine, University of Miami School of Medicine, and The Miami Veterans Administration Medical Center, Miami, Florida U.S.A.)
,
Ciancio, Gaetano
(Division of Transplantation, Department of Surgury, University of Miami School of Medicine, and The Miami Veterans Administration Medical Cent)
,
Esquenazi, Violet
,
Burke, George
,
Tzakis, Andreas
,
Miller, Joshua
AbstractMycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept™) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prografμ) as well in renal transplant patients, there ...
AbstractMycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept™) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prografμ) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (Neoral™). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF displayed significantly higher levels (Cmin and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune™ or Neoral™) and the same dose of MMF (50.2 ± 16.5 vs 32.1 ± 16.7 μg h/ml AUC, p < 0.02). Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose was increased by 50% (1.5 g bid). There were also significantly lower levels of the glucuronide metabolite of MPA (MPAG) (755 ± 280 vs 1230 ± 250 μg h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect) of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those receiving CsA. For each MLC assays and the MMF Dose. In addition, trough plasma from patients receiving tacrolimus and MMF was significantly more MLC inhibitory than from those receiving CsA or CsA microemulsion and equivalent-dose MMF. Culture media containing MPA and tacrolimus equal to clinical therapeutic trough concentratioins (10 ng/ml) were significantly more MLC inhibitory than CsA at equivalent clinical therapeutic trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.
AbstractMycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept™) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prografμ) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (Neoral™). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF displayed significantly higher levels (Cmin and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune™ or Neoral™) and the same dose of MMF (50.2 ± 16.5 vs 32.1 ± 16.7 μg h/ml AUC, p < 0.02). Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose was increased by 50% (1.5 g bid). There were also significantly lower levels of the glucuronide metabolite of MPA (MPAG) (755 ± 280 vs 1230 ± 250 μg h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect) of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those receiving CsA. For each MLC assays and the MMF Dose. In addition, trough plasma from patients receiving tacrolimus and MMF was significantly more MLC inhibitory than from those receiving CsA or CsA microemulsion and equivalent-dose MMF. Culture media containing MPA and tacrolimus equal to clinical therapeutic trough concentratioins (10 ng/ml) were significantly more MLC inhibitory than CsA at equivalent clinical therapeutic trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.
참고문헌 (14)
Kidney Int Sollinger 52 S14 1995 Mycophenolate mofetil
Pharm Res Lee 7 161 1990 10.1023/A:1015828802490 Bioavailability improvement of mycophenolic acid through amino ester derivitization
Drugs Noble 50 924 1995 10.2165/00003495-199550050-00009 Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral)
J Chromatog B Tsina 681 347 1996 10.1016/0378-4347(96)00038-2 High-performance liquid chromatographic method for the determination of mycophenolate mofetil in human plasma
Transplantation Sollinger 60 225 1995 10.1097/00007890-199508000-00003 Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients
Transplant Immunol Thompson 1 146 1993 10.1016/0966-3274(93)90009-W Effects of combined administration of FK506 and the purine biosynthesis inhibitors mizorbine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures
Transplantation Tanabe 58 23 1994 10.1097/00007890-199407000-00005 Combined immunosuppression therapy with low dose FK506 and anti-metabolites in rat allogeneic heart transplantation
AI-Helper
※ AI-Helper는 부적절한 답변을 할 수 있습니다.