tacrolimus and mycophenolic-acid-glucuronide

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.

Topics: Animals; Antimetabolites; Calcineurin Inhibitors; Cyclosporine; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Glucuronides; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

The early phase of MPA exposure has rarely been investigated after solid organ transplantation, especially in heart transplantation patients. We evaluated the association between exposure to mycophenolic acid (MPA), a main metabolite of mycophenolate mofetil (MMF), and clinical events within 3 months after heart transplantation.. Trough (C0) and area under the curve (AUC)0-12h levels of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were determined using high-performance liquid chromatography. Corresponding clinical endpoints included acute rejection or MMF-related adverse events (gastrointestinal symptoms, leucopenia, and anemia). AUC measurements (n=77) were collected from 21 patients. Dose-normalized C0 and AUC0-12h levels were used to evaluate the association between MPA or MPAG exposure and MMF-related adverse events.. No acute rejection or mortality occurred during the follow-up period. Twelve patients (57%) developed 13 MMF-related adverse events. The MMF dose was tapered from 2.50 g/day on D1 to 1.55±0.54 g/day on D90. Significantly higher levels of dose-normalized MPA C0 and AUC0-12h were associated with the events than with the absence of the events (C0: 1.04±0.42 vs. 0.84±0.85 µg/mL/g [p=0.047]; AUC0-12h: 20.37±3.21 vs. 14.97±1.13 µg × h/mL/g; [p=0.038]). Conclusions Dose-normalized MPA exposure may protect against MMF toxicity in the early stage after heart transplantation. The MMF dose can be decreased to near 1.5 g/day 3 months post-transplantation without jeopardizing patient safety; a well-planned, tapered MMF regimen should also be considered.

Topics: Adult; Area Under Curve; Female; Glucuronides; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

The aim of this study was to evaluate the influence of cyclosporine (CyA) and tacrolimus (Tac) on the pharmacokinetics of mycophenolic acid (MPA) and its glucuronides.. Kidney transplant recipients treated with mycophenolate mofetil and CyA (n=18) or Tac (n=17) in the stable phase were enrolled. The dependence of the trough concentration (C(0)) ratios of MPA acyl glucuronide (AcMPAG) to MPA (AcMPAG/MPA) and MPA phenol glucuronide (MPAG) to MPA (MPAG/MPA) on CyA C(0) or Tac C(0) was evaluated.. AcMPAG C(0) and MPAG C(0) were significantly higher in CyA- than Tac-treated recipients (P=0.04 and 0.02, respectively). AcMPAG/MPA and MPAG/MPA were significantly correlated to CyA C(0) (r=0.75, P<0.01 and r=0.81, P<0.01, respectively), but not to Tac C(0).. CyA increased AcMPAG/MPA as well as MPAG/MPA in a concentration-dependent manner, suggesting that higher CyA may cause AcMPAG-related adverse reactions. Tac did not alter pharmacokinetics of MPA and its glucuronides.

Topics: Adolescent; Adult; Cyclosporine; Female; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Young Adult

Concomitant cyclosporine interacts with mycophenolic acid (MPA) through inhibition of the biliary excretion of its glucuronide (MPAG). The aim of this study was to evaluate the influence of calcineurin inhibitors on the plasma disposition and urinary excretion of MPA and MPAG in kidney transplant recipients. Twelve recipients treated with tacrolimus and 18 treated with cyclosporine at 30 days after transplantation were enrolled. AUC from 0 to 12 hours (AUC(0-12)) of MPA was significantly higher in tacrolimus-treated than in cyclosporine-treated recipients. In contrast, there was no significant difference in MPAG AUC(0-12) between calcineurin inhibitor medications. Unbound fractions of MPA and MPAG did not change significantly in a comparison between the tacrolimus and cyclosporine treatments (0.90% vs 1.27% in MPA; 20.0% vs 19.3% in MPAG). The ratio of renal clearance to creatinine clearance (CL(R)/CL(Cr)) of MPA was significantly lower in tacrolimusthan in cyclosporine-treated recipients (0.054 vs 0.100). In contrast, no significant difference was observed in the CL(R)/CL(Cr) of MPAG between the tacrolimus and cyclosporine treatments (0.19 vs 0.18). In conclusion, concomitant calcineurin inhibitors influenced the urinary excretion of MPA but not MPAG in kidney transplant recipients. The results suggest the presence of renal tubular secretion in the urinary excretion process of MPA.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Enterohepatic Circulation; Enzyme Inhibitors; Female; Glucuronides; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

Mycophenolate mofetil [MMF, the prodrug of mycophenolic acid (MPA)] is usually administered at double doses with cyclosporine than with tacrolimus because it is believed that MPA exposure is lower during cyclosporine therapy. This study aimed to compare 12 hour, steady-state concentration-time profiles of MPA and its phenol- and acyl-glucuronide metabolites (MPAG and AcMPAG, respectively) in stable kidney transplant recipients maintained either on cyclosporine (n = 12) or tacrolimus (n = 12). During the absorption phase in the cyclosporine group, dose-normalized concentrations of total and free MPA were significantly higher but the overall area under the concentration-time curve (AUC0-12) was not significantly different. Additionally, exposure to AcMPAG was higher in the cyclosporine group (P < 0.05). Ten of 12 patients in the cyclosporine group were on ketoconazole therapy; however, the exposure to MPA or MPAG was not different when MMF was given orally to Sprague-Dawley rats with or without ketoconazole. In conclusion, cyclosporine modulates the disposition of MPA and metabolites differently from tacrolimus; however, patients on cyclosporine may not require double doses of MMF to achieve the same exposure.

Topics: Administration, Oral; Aged; Animals; Antibiotics, Antineoplastic; Area Under Curve; Cyclosporine; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glucuronides; Humans; Immunosuppressive Agents; Ketoconazole; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Rats; Rats, Sprague-Dawley; Tacrolimus

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Diarrhea; Dose-Response Relationship, Drug; Glucuronides; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Survival Analysis; Tacrolimus

Previous studies have shown that total-body clearance of mycophenolic acid (MPA) is increased and total MPA exposure decreased in renal allograft recipients with severe renal dysfunction. In contrast to these studies, other studies have associated renal impairment with higher MPA exposure. The reason for these inconsistencies is not clear.. In 120 renal allograft recipients with stable graft function and treated with a combination of mycophenolate mofetil, tacrolimus, and corticosteroids, clinical determinants of exposure to total MPA and its glucuronide metabolite MPA 7-O-glucuronide (MPAG) were investigated in a multivariate regression model at 3 (n=118) and 12 (n=63) months after transplantation.. Almost 50% of total MPA exposure could be explained by the final model, in which proteinuria, glomerular filtration rate, diabetes mellitus, and the mycophenolate mofetil dose were independent determinants of total MPA exposure. Lower glomerular filtration rate (GFR) was independently associated with higher MPA exposure both at 3 and 12 months after transplantation. GFR, alanine aminotransferase, and serum albumin levels and mycophenolate mofetil dose explained 69% of total MPAG exposure variability.. In stable renal recipients, total MPA exposure negatively associates with renal function, through accumulation of both MPA and MPAG in patients with moderately reduced renal allograft function. This is in contrast to severe graft dysfunction, where MPA clearance is higher due to increased free fraction of MPA, as shown in previous studies. The duality in the effect of graft function on MPA pharmacokinetics is of clinical importance, adjusting mycophenolate mofetil dose according to renal function might help to avoid side effects and improve efficacy.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glucuronides; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Prospective Studies; Tacrolimus; Time Factors

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (>6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C(0)). MPA C(0) in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C(0) was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C(0) of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C(0), MPAG C(0) and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period.

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Glucuronates; Glucuronides; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Time Factors

The aim of this study was to investigate the effect of time on pharmacokinetic (PK) parameters of mycophenolic acid (MPA) in the early post-transplant period in kidney recipients. MPA is the active metabolite of mycophenolate mofetil (MMF), which was introduced into clinical practice ten years ago.. Mycophenolate mofetil was co-administered with cyclosporin (CsA) in a subgroup of 23 patients and with tacrolimus (Tac) in a subgroup of 10 patients. MPA plasma concentration profiles were measured by a validated high performance liquid chromatography method 1 week, 2 and 3 months after transplantation.. Despite a comparable MMF dose, a large inter-patient variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.03-135.4 microg h/mL) and in predose concentrations (0.31-6.09 microg/mL) was observed. Patients with AUC > 35 microg h/mL showed better (P < 0.1) renal function than patients with AUC < 20 microg h/mL (mean creatinine concentration 1.48 +/- 0.12 vs. 3.35 +/- 0.4 mg/dL respectively). The total MPA trough and AUC did not correlate with biochemical parameters: leucocyte cell count and haematocrit. A higher trough level of the metabolite MPA glucuronide (MPAG) in the 1 week after transplantation was found when compared with the 3-month level (mean 150.1 +/- 146.7; range 17.1 to 560 vs. 75.8 +/- 40.0; range 27.3 to 174.2 microg/mL). The concentration of MPA, and MPA AUC values were significantly lower in patients receiving MMF and CsA than those receiving MMF and Tac during all three periods studied (P < 0.02). The influence of C(0) and MPA AUC values on the risk of graft rejection was investigated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for AUC was 0.847, whereas that of C(0) was 0.632.. The MPA AUC(0-12h) appeared to be the more effective PK parameter for predicting acute rejection. We recommend that routine MPA and MPAG therapeutic drug level monitoring should be an important part of MMF therapy.

Topics: Adolescent; Adult; Area Under Curve; Creatinine; Cyclosporine; Female; Glucuronides; Graft Rejection; Hematocrit; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Count; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

Topics: Adult; Aged; Area Under Curve; Bile; Bilirubin; Chromatography, High Pressure Liquid; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucuronates; Glucuronides; Half-Life; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Serum Albumin; Tacrolimus; Time Factors

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long-term tacrolimus-based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12-hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12-hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra- and intergroup PK of T were variable. The mean AUC0-12 of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.

Topics: Adult; Area Under Curve; Diarrhea; Dose-Response Relationship, Drug; Drug Interactions; Dyspepsia; Female; Glucuronates; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Nausea; Prodrugs; Tacrolimus; Vomiting

No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus. The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates.. Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs.. Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Black or African American; Cross-Sectional Studies; Drug Interactions; Drug Therapy, Combination; Female; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Sex Factors; Tacrolimus; Transplant Recipients; White People

BACKGROUND Mycophenolic acid (MPA) prodrugs are anti-proliferative immunosuppressive agents commonly used after organ transplantation. Although they are generally well tolerated by patients, adverse effects may occur. It is postulated that MPA metabolites could also contribute to these adverse effects. MATERIAL AND METHODS The objective of this study was the assessment of concentrations of total MPA and its metabolites, phenyl glucuronide (MPAG), acyl glucuronide (AcMPAG) and glucoside (GluMPA), using liquid chromatography combined with mass spectrometry (LC/MS/MS) in two groups: kidney transplant recipients and liver transplant patients. Associations of MPA and its metabolites with adverse effects were analyzed. RESULTS The study group consisted of 211 recipients of liver or kidney transplants who received immunosuppressive therapy, including MPA prodrugs. Multivariant analysis showed a positive influence of MPA on gastroenterotoxicity in kidney transplant recipients. In liver patients, gastroenterotoxicity was associated with lower MPAG concentrations. A positive influence of AcMPAG on bacterial infections in liver transplant patients was observed. In liver transplant recipients, a positive influence of MPA and a negative influence of GluMPA levels on the PLT count were revealed. MPA and its metabolites did not influence the hemoglobin levels in both groups. There were no significant relationships among MPA, its metabolites and WBC counts. CONCLUSIONS In kidney transplant recipients, total MPA trough concentration is associated with gastroenterotoxicity and its monitoring could have important role in management of gastrointestinal complications. The quantification of AcMPAG in liver recipients receiving MPA may be helpful in avoiding bacterial infections. GluMPA seems to have a toxic effect on thrombopoiesis.

Topics: Adult; Bacterial Infections; Cyclosporine; Female; Glucosides; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplant Recipients

1. The purpose of this study was to investigate the contribution of MRP2 to the efflux of mycophenolic acid (MPA), and its phenyl glucuronide (MPAG) and acyl glucuronide (AcMPAG) metabolites, using Madin-Darby canine kidney II cells stably transfected with human MRP2 gene (MDCKII/MRP2 cells). 2. Compared to parental MDCKII cells, MPAG was significantly translocated from basolateral (BL) to apical (AP) side in MDCKII/MRP2 cells, indicating MPAG is a substrate for MRP2. AcMPAG is highly translocated from BL to AP side in both cells, suggesting that AcMPAG is actively secreted possibly through an efflux transporter other than MRP2. Appreciable translocation of MPA was not observed in MDCKII/MRP2 cells. 3. Furthermore, using MRP2-expressing Sf9 membrane vesicles, the Michaelis-Menten constant (Km) value for MRP2-mediated MPAG transport was calculated at 224.2 ± 42.7 µM. In the vesicle system, cyclosporine, tacrolimus and sirolimus did not inhibit the uptake of MPAG via MRP2. 4. These findings indicate that only MPAG not MPA and AcMPAG is a substrate for MRP2 and that the interaction between MPAG and concomitantly administered immunosuppressive agents does not occur at MRP2 level.

Topics: Adenosine Triphosphate; Animals; Biological Transport; Cell Membrane; Cell Membrane Permeability; Cyclosporine; Diffusion; Dogs; Epithelial Cells; Glucuronides; Humans; Madin Darby Canine Kidney Cells; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mycophenolic Acid; Sirolimus; Tacrolimus; Transport Vesicles

The pharmacokinetics of both tacrolimus and mycophenolic acid in renal transplant recipients on a corticosteroid-free regimen was evaluated.. Upon administration of steady-state morning tacrolimus and mycophenolate mofetil doses, 28 patients for whom at least three months had passed after renal transplantation underwent serial blood sample collection over a 12-hour dosing period. Whole blood concentrations of tacrolimus were measured, as were mycophenolic acid, mycophenolic acid 7-0-glucuronide (MPAG), and acyl glucuronide MPAG (AcMPAG) concentrations. Pharmacokinetic parameters were then analyzed by conventional noncompartmental modeling.. The mean ± S.D. pharmacokinetic parameters for tacrolimus, normalized to a dose of 1 mg, were as follows: area under the concentration-time curve (AUC), 52.6 ± 24.8 μg · hr/L/mg; maximum concentration (C(max)), 8.0 ± 3.3 μg/L/mg; time to C(max) (t(max)), 1.8 ± 1.0 hr; and minimum concentration (C(min)), 2.6 ± 1.4 μg/L/mg. The mean ± S.D. pharmacokinetic parameters for mycophenolic acid, normalized to a mycophenolate mofetil dose of 1 g, were AUC, 26.9 ± 13.2 μg ·hr/mL/g; C(max), 17.5 ± 5.4 μg/mL/g; t(max), 0.9 ± 0.6 hr; and C(min), 1.5 ± 1.1 μg/mL/g. The free fraction of mycophenolic acid was 1.8% ± 0.7%. AUC ratios of MPAG:mycophenolic acid and AcMPAG:mycophenolic acid were 13.0 ± 5.8 and 0.1 ± 0.2, respectively.. Overall exposure and C(min) values for tacrolimus were similar but C(max) values were higher than those documented in renal transplant patients treated with corticosteroid-based regimens. This may have clinical implications in corticosteroid-free patients experiencing symptoms of tacrolimus toxicity despite trough levels within target ranges. Mycophenolic acid exposure increased with time, but AUC values fell within the range expected for patients receiving concurrent corticosteroids.

Topics: Adult; Area Under Curve; Cross-Sectional Studies; Female; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Prospective Studies; Tacrolimus

The factors affecting the pharmacokinetics of free mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) are still unclear. The aim of this study was to evaluate the influence of cyclosporine on the pharmacokinetics of free MPA and MPAG.. Seventy-seven kidney transplant recipients (23 were in an initial phase and 54 in a stable phase; 41 were treated with cyclosporine and 36 with tacrolimus) were enrolled. Free and total MPA and MPAG were determined using HPLC. The correlations between free and total predose concentrations (C(0) ) of MPA or MPAG were evaluated separately in patients receiving calcineurin inhibitor medications.. Serum concentration of albumin was lower in the initial phase than in the stable phase. A higher ratio of free MPAG C(0) to free MPA C(0) was observed in cyclosporine-treated than tacrolimus-treated kidney transplant recipients. Free MPA C(0) correlated weakly with total MPA C(0) in kidney transplant recipients treated with cyclosporine in the initial phase (ρ= 0·53, P = 0·06).. Cyclosporine increased the ratio of free MPAG C(0) to free MPA C(0) and varied the free fraction of MPA in the hypoalbuminaemic kidney transplant recipients in the initial phase.

Topics: Adult; Area Under Curve; Chromatography, High Pressure Liquid; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Glucuronides; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Serum Albumin; Tacrolimus; Time Factors

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration-time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on

Topics: Adult; Aged; Area Under Curve; Biotransformation; Computer Simulation; Creatinine; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Enterohepatic Circulation; Female; Glucuronides; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Protein Binding; Randomized Controlled Trials as Topic; Reproducibility of Results; Serum Albumin; Tacrolimus; Young Adult

The polymorphic enzyme UGT2B7 metabolizes mycophenolic acid into acyl-mycophenolic acid-glucuronide (AcMPAG), a presumably toxic metabolite. This study aimed at investigating in vitro and in vivo the impact on AcMPAG production of: (i) the UGT2B7 gene G-842A single nucleotide polymorphism, in complete linkage disequilibrium with most other known single nucleotide polymorphisms in the promoter region of this gene and with the C802T single nucleotide polymorphism in exon 2 (UGT2B*2); and (ii) of the other immunosuppressants given to renal transplant patients in association with mycophenolate mofetil.. We compared the production of AcMPAG by human liver microsomes genotyped for the UGT2B7 G-842A and C802T single nucleotide polymorphisms, and plasma AcMPAG concentrations in genotyped renal transplant patients administered mycophenolate mofetil associated with sirolimus (n=40), tacrolimus (n=24) or cyclosporin (n=28) and decreasing doses of corticosteroids, over the first 3 months after transplant. The effect of corticosteroids was also investigated in vitro using rats' liver microsomes.. The two polymorphisms studied were in complete reverse linkage disequilibrium. AcMPAG production was 1.25 and 1.56-fold higher in G-842A and -842AA human liver microsomes, respectively, compared with GG-842 human liver microsomes (P=0.01). Enzyme kinetics showed 1.4 and 3.7-fold higher Vmax in the respective pools of human liver microsomes. Km values were 0.20, 0.25 and 0.44 mmol/l for the GG-842, G-842A and -842AA genotypes, respectively. This clear increase in Vmax is in favor of the implication of the promoter region polymorphisms, whereas the slighter increase in Km might be due to the UGT2B7*2 single nucleotide polymorphism. Consistently, the UGT2B7 genotype significantly influenced AcMPAG area under the curve (AUC0-9 h)/dose in patients on sirolimus at months 1 and 3 after transplant (P=0.04 for both). No effect was observed in patients on tacrolimus and possibly also on cyclosporin, maybe owing to pharmacokinetic interaction with mycophenolate. AcMPAG production was increased in corticosteroid-induced rat liver microsomes, consistent with the observed in-vivo decrease of mycophenolic acid metabolites AUC0-9 h/dose with time after transplant.. Both UGT2B7 polymorphisms and co-medications significantly influenced AcMPAG production, but cyclosporin and tacrolimus hindered the phenotypic impact of this trait.

Topics: Acylation; Administration, Oral; Adult; Animals; Area Under Curve; Chromatography, High Pressure Liquid; Cyclosporine; Drug Monitoring; Exons; Genotype; Glucuronides; Glucuronosyltransferase; Humans; Immunosuppressive Agents; In Vitro Techniques; Kidney Transplantation; Male; Microsomes, Liver; Mycophenolic Acid; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Binding; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus

Matrix effects can profoundly reduce the performance of electrospray ionization mass spectrometry. Preliminary observations indicated that the methanol used in the mobile phase could be a source of differential ionization or ion suppression.. Drug stability studies, analysis of biological extracts, mixing experiments, and postcolumn infusions were used to test 9 commercial methanols for ionization differences in liquid chromatography-tandem mass spectrometry assays for immunosuppressants. Area responses for the drugs and internal standards were compared for mobile phases prepared with each selected methanol. Postcolumn infusion experiments were performed to confirm the degree of ionization differences occurring at the ion source, and to evaluate the proportions of ammonium, sodium, and potassium adducts.. The decrease in signal for the immunosuppressant drugs was shown to result from differential ionization associated with the selected methanols. Product ion intensity varied by 10-fold among the methanols tested. For sirolimus, tacrolimus, and mycophenolic acid, the percentage change in ionization was the same for the drug and its corresponding internal standard. Postcolumn sirolimus infusion evaluation revealed that a 1000-fold analyte concentration difference did not affect ionization. The proportions of ammonium, sodium, and potassium adducts of sirolimus precursor ions differed in relation to the source of methanol.. Organic solvents used in mobile phases and extract preparation of biological samples may be associated with ion suppression, affecting adduct formation and assay sensitivity.

Topics: Chromatography, Liquid; Glucuronides; Humans; Immunosuppressive Agents; Methanol; Mycophenolic Acid; Sensitivity and Specificity; Sirolimus; Solvents; Spectrometry, Mass, Electrospray Ionization; Tacrolimus; Tandem Mass Spectrometry

Hepatic regeneration is very critical to the success of living donor liver transplantation, which allows a reduced size liver to grow in size to accommodate the requirements of both the donor and the recipient. The objectives of this study were to evaluate 1) the hepatic metabolism of the two immunosuppressive drugs, tacrolimus and mycophenolic acid (MPA), and 2) the pharmacokinetics of tacrolimus and mycophenolic acid at various time points after initiation of hepatic regeneration by partial hepatectomy in rats. The hepatic intrinsic clearance of tacrolimus was decreased to 70% and 51% of the control level at the 24th h and the 6th day, respectively, but returned to normal level by day 14. The total body clearance of tacrolimus was reduced transiently but recovered completely by day 18. The hepatic intrinsic clearance of MPA was decreased to 52% and 51% of that in control rats at the 24th h and the 6th day, respectively, but recovered to normal level by day 14. The total body clearance of MPA was reduced at the 24th h but recovered by day 6. The magnitude of reduction in the clearance of tacrolimus and MPA was much smaller than what was predicted from in vitro data. The elimination clearance of MPA glucuronide was also impaired during hepatic regeneration but recovered to normal level with time. In conclusion, the pharmacokinetics of tacrolimus and mycophenolic acid were altered during hepatic regeneration but recovered completely at different rates over time. Caution must be exercised in extrapolating in vitro data to in vivo conditions during hepatic regeneration.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; ATP-Binding Cassette Transporters; Glucuronates; Glucuronides; Hepatectomy; Immunosuppressive Agents; Intestine, Small; Kidney; Liver; Liver Regeneration; Male; Microsomes; Microsomes, Liver; Models, Animal; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tacrolimus; Time Factors

The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients.. Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant.. Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4).. The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Area Under Curve; Chromatography, High Pressure Liquid; Cyclosporine; Female; Glucuronates; Glucuronides; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Period; Protein Binding; Tacrolimus

The onset of diarrhea after the administration of mycophenolate mofetil (MMF) is possibly associated with the biliary excretion of its metabolite, mycophenolic acid glucuronide (MPAG). This study was undertaken to clarify the mechanism underlying the biliary excretion of MPAG. Intravenously administered mycophenolic acid (MPA, 5 mg/kg) rapidly disappeared from plasma and was efficiently excreted as MPAG in the bile of Wistar (26% of dose) and Sprague-Dawley rats (21% of dose) over 1 h. On the other hand, in spite of the rapid disappearance of MPA from plasma, the biliary excretion of MPAG was very limited in Eisai hyperbilirubinemic rats (EHBRs), which display mutations in multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter, and constituted only 0.5% of dose. Instead, high levels of MPA were noted in the plasma of EHBRs. Intravenous administration of CsA (5 mg/kg) to Wistar rats significantly lowered the biliary excretion of MPAG. However, intravenously administered tacrolimus (0.1 mg/kg) failed to produce such effect. In conclusion, it is suggested that there is an efficient MPAG transport mediated by Mrp2 on the bile canalicular membrane of rat hepatocytes and that the therapeutic range of CsA potentially interferes with Mrp2. However, the therapeutic range of tacrolimus does not inhibit the transporter. Thus, it should be noted that MMF coadministered with tacrolimus instead of CsA might increase the occurrence of diarrhea related to the biliary excretion of MPAG in transplant recipients.

Topics: Animals; Biliary Tract; Cyclosporine; Glucuronates; Glucuronides; Immunosuppressive Agents; Infusions, Intravenous; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tacrolimus

The establishment of a rationale for therapeutic drug monitoring for mycophenolic acid (MPA) and outlining a therapeutic window remains a challenging task in renal transplantation. Furthermore, the pharmacokinetic characteristics of free and total MPA and its glucuronides depend directly or indirectly on graft function and the type of co-administered calcineurin-inhibitor.. The authors conducted a prospective 12-month multicenter pharmacokinetic study on MPA (MPA, free MPA, free fraction MPA) and its metabolites (MPAG, Acyl-MPAG). The aim of this study was to examine the long-term pharmacokinetic characteristics of MMF when combined with tacrolimus in renal allograft recipients and to identify a possible relationship between these pharmacokinetic parameters and clinical outcome parameters.. They have demonstrated that in renal transplant recipients MPA, free MPA, Acyl-MPAG and MPAG have a particular pharmacokinetic profile when combined with tacrolimus which differs from the combination with CsA. They could not establish a relationship between pre-dose trough concentration of MPA and its metabolites and clinical efficacy endpoints and drug-related adverse events, except for anemia.. These findings suggest that trough plasma concentration monitoring of MPA and its metabolites might not provide a useful clinical tool for guiding MMF dose adjustments to avoid drug-related toxicity. More extensive pharmacokinetic measurements like area under the concentration curves might be necessary for routine therapeutic drug monitoring of MMF.

Topics: Adult; Aged; Area Under Curve; Drug Therapy, Combination; Female; Glucuronates; Glucuronides; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Transplantation, Homologous

Determinants of the wide interindividual variability of the pharmacokinetics of mycophenolic acid (MPA) in 21 stable pediatric liver transplant recipients were investigated in relation to the kinetics of the drug's major phenolic glucuronide metabolite (MPAG), cyclosporin (CsA), or tacrolimus (Tac) co-medication and liver and renal function. Trough concentrations (C(0) ) most reliably predicted the area under the curve (AUC) of 0-7 hours MPA plasma concentrations (r (2) = 0.650). Co-medication with CsA demanded higher MPA mofetil (MMF) doses to achieve equivalent trough levels than Tac (362 vs. 178 mg per mg/L, P= 0.004). Median MPA C(0) (range) was significantly lower during CsA co-therapy when corrected for MMF dose (2.8 vs. 5.6 mg MPA/L for Tac, P= 0.006). The AUC of MPAG was correspondingly higher during CsA co-medication (229 vs. 94 mg/L/h for Tac, P = 0.012) with the MPA-to-MPAG ratio at C(0) correspondingly lower (0.10 vs. 0.14, respectively, P = 0.04). This suggested contrasting effects of CsA and Tac on MPA glucuronidation or its excretion and enterohepatic recirculation. MPAG AUC was correlated to body weight and creatinine clearance. Children with elevated aspartate transaminase (AST; but with no evidence of rejection on liver biopsy, n = 7) had significantly lower MPA trough levels compared with those in whom AST was normal (0. 77 vs. 1.76 mg/L, P = 0.05), but there was no difference in the MMF dose per body weight. Examination of the MPA profiles in these subjects showed significantly lower MPA concentrations from 120 minutes after dose until the end of the 7-hour profile and suggest an accelerated clearance or decreased enterohepatic recirculation.)

Topics: Adolescent; Area Under Curve; Chi-Square Distribution; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Glucuronates; Glucuronides; Graft Rejection; Humans; Liver Transplantation; Male; Mycophenolic Acid; Statistics, Nonparametric; Tacrolimus

Mycophenolate mofetil (MMF), an immunosuppressant drug used in organ transplantation to prevent rejection, is being used increasingly in association with cyclosporine and tacrolimus. Mycophenolic acid (MPA) is primarily metabolized in the liver to its 7-O-glucuronide (MPAG) derivative. The concentrations of MPAG in serum are many times the concentrations of MPA. Although MPAG has not shown immunosuppressant activity, it was postulated that it could displace MPA from its binding sites on albumin and hence increase the biologic effects of MPA. This effect could be important for patients with acute renal failure; under this condition, MPAG was shown to accumulate. The goal of this study was to document the MPAG/MPA concentration ratio in 100 renal transplant patients under a mixed immunosuppressive therapy. Further, the study addressed the question of whether MPAG can displace MPA in vivo from bound albumin in a representative renal transplant patient population under immunosuppressive therapy. Levels of MPAG and MPA were measured by high-performance liquid chromatography. The distribution of the ratios was not parametric as it tailed toward elevated values. After a square root transformation of the data, parametric analysis was possible. The average MPAG/MPA ratio was 15.0 +/- 2.2 for men versus 7.7 +/- 0.9 for women. Men treated with MMF and tacrolimus showed a lower ratio than patients treated with MMF and cyclosporine, confirming that tacrolimus inhibits glucuronidation of MPA. Further, it was determined that at physiologic concentrations, MPAG does not increase the amount of free MPA. Because MPAG can favor the elimination of MPA, it can be concluded that gender differences and cotreatment with tacrolimus must be taken into consideration when MMF is being administered.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Creatinine; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Female; Glucuronates; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Sex Characteristics; Tacrolimus

The aim of the study was to evaluate the effect of t-tube clamping on the pharmacokinetics of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) in primary liver transplant recipients treated with tacrolimus as the primary immunosuppressive drug. We evaluated the pharmacokinetics of MPA and its primary metabolite, mycophenolic acid glucuronide (MPAG), before and after clamping the t-tube in 8 primary liver transplant recipients treated with oral MMF and tacrolimus. The concentration of MPA and MPAG in plasma, bile, and urine samples obtained over one dosing interval was measured by high-pressure liquid chromatography. Pharmacokinetic parameters of MPA estimated before and after clamping the t-tube were compared to evaluate any significant differences at a P of.05 or less. There were no significant differences in the time to reach peak plasma concentration (1.8 +/- 1.7 v 1.0 +/- 0.5 hours), trough plasma concentration of MPA (1.1 +/- 1.4 v 1.4 +/- 1.1 microgram/mL), peak plasma concentration of MPA (10.6 +/- 7.5 v 11.1 +/- 4.6 microgram/mL), area under the plasma concentration-versus-time curve (AUC) (40.1 +/- 31.9 v 43.2 +/- 21.1 microgram/mL/h) of MPA, or the percentage of MPA that is free or unbound in the plasma (3.9% +/- 1.6% v 4.1% +/- 3.0%). There was also no significant difference in the ratio of the AUC of MPAG to MPA. These observations suggest that t-tube clamping does not affect the kinetics of MPA or MPAG and that no dosing alterations of MMF are required when the t-tube is clamped in liver transplant recipients.

Topics: Administration, Oral; Adult; Aged; Bile; Constriction; Equipment and Supplies; Female; Glucuronates; Glucuronides; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Tacrolimus