***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE 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 . METHOD 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 vali date d high performance liquid chromatography method 1 week , 2 and 3 months after transplantation . RESULTS 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 . CONCLUSIONS 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 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 BACKGROUND Significant relationships between the mycophenolic acid ( MPA ) area under the concentration-time curve ( AUC(0 - 12h ) ) and the risks for acute rejection and side effects have been reported . We developed a practical method for estimation of MPA AUCs . Regression equations were developed using repeated cross-validation for r and omly chosen subsets , characterized statistically , and verified for acceptable performance . METHODS Twenty-one renal transplant patients receiving 0.5 or 1.0 g of mycophenolate mofetil twice daily and concomitant tacrolimus provided a total of 50 pharmacokinetic profiles .  MPA concentrations were measured by a vali date d HPLC method in 12 plasma sample s collected at predose and at 30 and 60 min ; 2 , 3 , 4 , 6 , 8 , 9 , 10 , 11 , and 12 h ; 1 and 2 weeks ; and 3 months after transplantation . Twenty-six 1- , 2- , or 3- sample estimation models were fit ( r(2 ) = 0.341 - 0.862 ) to a r and omly selected subset of the profiles using linear regression and were used to estimate AUC(0 - 12h ) for the profiles not included in the regression fit , comparing those estimates with the corresponding AUC(0 - 12h ) values , calculated with the linear trapezoidal rule , including all 12 timed MPA concentrations . The 3- sample models were constrained to include no sample s past 2 h. RESULTS The model using c(0h ) , c(0.5h ) , and c(2h ) was superior to all other models tested ( r(2 ) = 0.862 ) , minimizing prediction error for the AUC(0 - 12h ) values not included in the fit ( i.e. , the cross-validation error ) . The regression equation for AUC estimation that gave the best performance for this model was : 7.75 + 6.49c(0h ) + 0.76c(0.5h ) + 2.43c(2h ) . When we applied this model to the full data set , 41 of the 50 ( 82 % ) estimated AUC values were within 15 % of the value of AUC(0 - 12h ) calculated using all 12 concentrations . CONCLUSIONS This limited sampling strategy provides an effective approach for estimation of the full MPA AUC(0 - 12h ) in renal transplant patients receiving concomitant tacrolimus therapy Mycophenolate mofetil ( MMF ) is a prodrug immunosuppressant with a high oral bioavailability . Enterohepatic cycling of a glucuronide derivative of MMF contributes substantially to the bioavailability , but is dependent on bacterial deglucuronidation by intestinal flora . This study aims to determine whether an antibiotic regimen with activity against such organisms reduces the bioavailability of MMF  by impairing enterohepatic cycling . In a prospect i ve trial , 6 liver transplant recipients were administered MMF and a 21-day antibiotic regimen for selective bowel decontamination ( SBD ) .  Time-concentration profiles of the pharmacologically active metabolite , mycophenolic acid ( MPA ) , were obtained during and after the SBD regimen . The bioavailability of MPA was reduced during compared with after the regimen ( 14.5 + /- 3.5 v 21.1 + /- 9.8 mg . h/mL ; P = .07 ) . The most pronounced contribution to this reduction was observed from 6 hours onward ( 2.4 + /- 1.4 v 5.6 + /- 4.4 mg . h/mL ; P < .05 ) . The presence of secondary maxima in the time-concentration profiles of MPA after , but not during , SBD indicates that enterohepatic cycling may be inhibited during SBD and restored afterward . Enterohepatic cycling may contribute 7 % to 54 % ( mean , 29 % ) of the bioavailability of MPA . We conclude that the bioavailability of MMF  may be reduced when SBD is used , and the reduction is likely to result from the interruption of enterohepatic cycling . This mechanism should be taken into consideration not only during SBD , but in any clinical setting combining MMF and broad-spectrum antibiotics BACKGROUND Mycophenolate mofetil ( MMF ) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A ( CsA ) or tacrolimus ( Tc ) . An increase in plasma mycophenolic acid ( MPA ) has been shown in patients receiving Tc-MMF combination therapy  compared with CsA-MMF combination therapy at the same dose of MMF . The aim of this prospect i ve study was to assess the pharmacokinetic/pharmacodynamic ( PK/PD ) relationship for MPA in kidney transplant patients receiving low-dose MMF ( 500 mg twice a day ) in combination with Tc .  METHODS Adult kidney transplant recipients ( n = 51 ) were included . MPA-PK profiles ( blood sampling at 0 , 0.5 , 1 , 2 , 4 , 6 , and 12 h after MMF oral dose ) were obtained within the first 2 weeks after transplantation , 3 months after grafting , and at every adverse clinical event [ side effect or acute rejection ( AR ) ] . All patients received Tc , MMF ( 500 mg twice a day ) , and steroids . RESULTS Thirty patients ( 59 % ) had uneventful outcomes , and 21 patients had 33 episodes of MPA-related side effects ; only 3 patients had AR . A total of 78 MPA-PK profiles  were obtained . The following PK parameters were increased in the side-effects group compared with the non-side effects group : mean MPA c(min ) , 2.63 + /- 1.58 vs 1.75 + /- 0.82 mg/L ( P = 0.016 ) ; mean c(30 ) , 10.47 + /- 6.27 vs 7.66 + /- 8.95 mg/L ( P = 0.009 ) ; mean c(60 ) , 9.67 + /- 5.42 vs 5.83 + /- 2.6 mg/L ( P = 0.0002 ) ; mean area under the MPA time-concentration curve from 0 to 12 h [ MPA-AUC((0 - 12 ) ) ] , 48.38 + /- 18.5 vs 36.04 + /- 10.82 mg . h/L ( P = 0.0006 ) ; mean dose-normalized MPA-AUC , 0.16 + /- 0.05 vs 0.12 + /- 0.04 ( mg . h/L)/(mg/m(2 ) ) ( P = 0.0015 ) . For the three AR patients , MPA concentrations obtained at the time of AR revealed MPA c(min ) values of 1.86 , 1.76 , and 3.83 mg/L , respectively , and MPA-AUC((0 - 12 ) ) values of 37.7 , 24.9 , and 104.9 mg . h/L. The threshold of toxicity was 3 mg/L ( sensitivity , 38.7 % ; specificity , 91.5 % ) for c(min ) , 8.09 mg/L for maximum MPA concentration during the first hour ( sensitivity , 77.8 % ; specificity , 67.4 % ) , and 37.6 mg . h/L for MPA-AUC((0 - 12 ) ) ( sensitivity , 83.3 % ; specificity , 59.6 % ) . CONCLUSIONS These results demonstrate the relationship between plasma MPA concentrations and toxicity . High c(min ) , c(30 ) , and c(60 ) values as well as AUC((0 - 12 ) ) are associated with increased risk for side effects . These values may have an importance in a routine monitoring program BACKGROUND HPLC is currently the preferred method for accurate measurement of mycophenolic acid ( MPA ) . This study was design ed to vali date the Emit compared with HPLC in relation to clinical outcome measurements . METHODS Pediatric renal-transplant recipients ( n = 50 ) on an immunosuppressive triple regimen consisting of cyclosporin A , prednisone , and mycophenolate mofetil ( 600 mg/m(2 ) twice per day ) were investigated in an open-label prospect i ve study . Pharmacokinetic profiles over 12 h were obtained at 1 week , 3 weeks , 3 months , and 6 months posttransplant . Plasma MPA was measured by both reversed-phase HPLC and the Emit immunoassay . RESULTS There was an association between the risk of acute rejection episodes and low area under the curve values from t(0 ) to t(12h ) ( AUC(0 - 12 ) ) for MPA ( MPA-AUC(0 
    Output:
    
RESULTS The majority of studies are retrospective in nature , demonstrating good correlation between the full total MPA area-under-the-curve and the risk of acute rejection , but not toxicity .
Free MPA levels may better predict toxicity .
Single-point parameters , in particular trough levels , show poor correlation with the risk of acute rejection and toxicity , and in prospect i ve studies do not improve clinical outcomes .
Limited sampling strategies using sample s from the first few hours postdose allow good prediction of the full area-under-the-curve , and monitoring using these strategies may improve clinical outcomes .