Pharmacokinetics (PK) of intravenous mycophenolate mofetil (MMF) in liver transplant patients.

Hébert, Mary F.; Chang, Tim; Linna, T. Juhani; Hale, Michael; Roberts, John P.

doi:10.1038/sj.clpt.1996.235

Cited by 6 publications

(13 citation statements)

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“…Prior to this report there has been only 1 short report on the pharmacokinetics of MPA after IV administration of MMF in LTx patients. The AUC of MPA after administration of 1.75 gm MMF at 24 hours after LTx was reported to be 42.85 ± 21.7 μg · hr/mL in 6 patients 30. When the AUC data were normalized to the dose administered, the value is similar to what is observed in the present report.…”

Section: Discussionsupporting

confidence: 89%

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

et al. 2007

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The bioavailability of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) has been reported to be more than 90% in healthy volunteers, and in kidney and thoracic organ transplant patients. Such information is limited in liver transplant (LTx) patients. The present study compares the pharmacokinetics of MPA after intravenous (IV) and oral administrations of MMF in LTx recipients. Pharmacokinetic parameters were calculated using WinNonlin software. A total of 12 deceased donor LTx patients initially received IV MMF and were switched to oral MMF after 2-7 days (mean, 3.3 Ϯ 1.7) when oral feeds were started. Multiple blood samples were drawn immediately prior to and after IV or oral MMF and the plasma concentration of MPA was measured. The mean peak plasma concentrations and the area under the plasma concentration vs. time curve (AUC) were significantly higher after IV MMF compared to oral MMF (peak plasma concentrations of 10.7 Ϯ 2.1 g/mL for IV vs. 4.5 Ϯ 2.8 g/mL for oral; P ϭ 0.0001; and AUC of 28.9 Ϯ 7.1 g ⅐ hr/mL for IV vs. 12.8 Ϯ 4.2 g ⅐ hr/mL for oral; P ϭ 0.0001). The oral bioavailability of MPA was 48.5 Ϯ 18.7%. The systemic clearance, half-life, and steady state volume of distribution of MPA were 26.9 Ϯ 6 L/hour, 5.5 hours, and 85 liters, respectively. The terminal disposition half-life was not significantly different between the 2 routes of administration. In conclusion, during the early postoperative period, LTx recipients have MPA exposure with oral MMF of less than half that of IV MMF. Use of IV MMF immediately post-LTx may provide an immunological advantage. Liver Transpl 13: 791-796, 2007.

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Section: Discussionsupporting

confidence: 89%

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

et al. 2007

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“…These studies have demonstrated wide variations in the kinetics of MPA when a fixed dose of MMF was administered to the patients 15,16,24–31 . However, limited information is available on the pharmacokinetics of MPA in liver transplant patients 14,32–34 …”

Section: Discussionmentioning

confidence: 99%

Intraindividual and Interindividual Variations in the Pharmacokinetics of Mycophenolic Acid in Liver Transplant Patients

Pisupati

Jain

Burckart

et al. 2005

The Journal of Clinical Pharma

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The authors evaluated the intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid after oral administration of mycophenolate mofetil in 10 liver transplant patients. Mycophenolic acid and its metabolite, mycophenolic acid glucuronide, were measured in plasma and urine by high-pressure liquid chromatography. The plasma protein binding of mycophenolic acid was determined by ultrafiltration. The maximum concentration of mycophenolic acid in plasma increased significantly (P < or = .05) with time from 9.1 +/- 7.2 microg/mL (<1 week) to 36.7 +/- 15.6 microg/mL (1 month). The area under the plasma concentration versus time curve of mycophenolic acid also increased significantly with time, from 50.8 +/- 42.1 microg x h/mL to 118.0 +/- 57.6 microg x h/mL (P < or = .05). The plasma protein binding of mycophenolic acid increased from 92% to 98%, and the apparent oral clearance [CL/F] decreased from 32.9 +/- 21.4 L/h during the first study period to 9.0 +/- 4.4 L/h (P < or = .05) during the third study period. The apparent intrinsic clearance of mycophenolic acid did not change significantly over time. The ratio of the area under the curve of mycophenolic acid glucluronide to mycophenolic acid in plasma decreased with time (25.5 +/- 21.2 vs 8.0 +/- 3.3) but did not reach statistical significance. The increased binding of mycophenolic acid to plasma proteins with time after transplantation appeared to contribute to the intraindividual variation, whereas differences in the ability of the liver to metabolize mycophenolic acid between patients appear to contribute to the large interindividual variation in the pharmacokinetics of mycophenolic acid. The observations in this study support the concept of measuring the unbound concentration of mycophenolic acid to optimize immunosuppressive drug therapy with mycophenolic acid.

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“…The presence of secondary maxima in the time-concentration profiles of MPA after cessation of SBD as opposed to during SBD indicates that enterohepatic cycling of MPA was inhibited by SBD and restored when SBD was withdrawn. The contribution of these secondary maxima is reflected by a significant increase in AUC [6][7][8][9][10][11][12] . However, the secondary maximum never was very pronounced.…”

Section: Discussionmentioning

confidence: 99%

“…Bioavailability was expressed as the trapezoidal area under the curve (AUC). The AUC was calculated for the complete 12-hour sampling period as AUC 12 , and for the 0-to 6-hour and 6-to 12-hour periods separately as AUC 6 and AUC [6][7][8][9][10][11][12] , respectively. AUC 6 was taken as a measure of the primary absorption of MMF, whereas AUC 6-12 was assumed to reflect the contribution of enterohepatic cycling.…”

Section: Methodsmentioning

confidence: 99%

“…However, a significant amount of MPAG is excreted into the bile and, after bacterial deglucuronidation, subsequently reabsorbed as MPA. 6,8 In the concentration-time profile of MPA, this enterohepatic cycling of MPAG is responsible for the occurrence of secondary maxima, usually approximately 6 to 12 hours postdose. 7,9,10 Consequently, mechanisms affecting enterohepatic cycling may potentially interact with the pharmacokinetics of MMF.…”

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confidence: 99%

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The effect of selective bowel decontamination on the pharmacokinetics of mycophenolate mofetil in liver transplant recipients

Schmidt

Rasmussen²,

Nørrelykke

et al. 2001

Liver Transplantation

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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 prospective 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 ⅐ 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 ⅐ 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. (Liver Transpl 2001;7: 739-742.)

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Pharmacokinetics (PK) of intravenous mycophenolate mofetil (MMF) in liver transplant patients.

Abstract: Clinical Pharmacology & Therapeutics (1996) 59, 184–184; doi:

Cited by 6 publications

References 0 publications

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

Intraindividual and Interindividual Variations in the Pharmacokinetics of Mycophenolic Acid in Liver Transplant Patients

The effect of selective bowel decontamination on the pharmacokinetics of mycophenolate mofetil in liver transplant recipients

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