Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

Naito, Takafumi; Shinno, Kazuko; Maeda, Toshio; Kagawa, Yoshiyuki; Hashimoto, Hisakuni; Otsuka, Atsushi; Takayama, Tatsuya; Ushiyama, Tomomi; Suzuki, Kazuo; Ozono, Seiichiro

doi:10.1248/bpb.29.275

Cited by 46 publications

(28 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9,34,41,42 In the present investigation, exposure to AcMPAG was somewhat higher in liver transplant recipients on low-dose CSA than in those patients on low-dose TAC, although this did not reach statistical significance. However, AcMPAG concentrations at 2-hour postdose, the time point at which the maximum CSA and TAC concentrations occurred, and also at 4-hour postdose were significantly higher in those patients on CSA.…”

Section: Discussioncontrasting

confidence: 76%

Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolites in Stable Adult Liver Transplant Recipients With Renal Dysfunction on a Low-Dose Calcineurin Inhibitor Regimen and Mycophenolate Mofetil

Beckebaum¹,

Armstrong²,

Cicinnati³

et al. 2009

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

Low-dose calcineurin inhibitors (CNIs) in combination with a fixed dose (2 g/d) of mycophenolate mofetil (MMF) are a strategy to minimize exposure to cyclosporine (CSA) or tacrolimus (TAC) and thus reduce CNI-related side effects. This study compared the pharmacokinetics (PK) of mycophenolic acid (MPA) and its glucuronide metabolites in stable adult liver transplant recipients with moderately impaired renal function converted from a standard to a low-dose CNI regimen in combination with a fixed dose of MMF. Full 12-hour PK profiles of MPA, free MPA, the aryl glucuronide (MPAG), and the acyl glucuronide (AcMPAG) were obtained from 30 stable liver transplant patients on low-dose CNI (CSA, n = 12; TAC, n = 18) therapy at least 3 months after initiation of low-dose therapy. Predose CSA and TAC concentrations (quantified by liquid chromatography-tandem mass spectrometry) ranged from 17 to 35 and 1.1 to 3.7 microg/L, respectively. The PK variables for MPA, MPAG, AcMPAG, and free MPA displayed wide interindividual variability. Of note was the observation that there were no significant differences in the exposure to MPA, MPAG, and free MPA between the CSA and TAC groups. MPA area under the concentration-time curves (AUCs) ranged from 31.8 to 102.1 (median: 52.9) mg.h(-1).L(-1) in the CSA group and from 22.9 to 144.8 (median: 55.9) mg.h(-1).L(-1) in the TAC group. The AcMPAG AUC on patients under low-dose CSA therapy was higher than that observed under patients on low-dose TAC therapy, although this did not quite reach statistical significance (P = 0.057). Patients receiving CSA had a significantly higher AcMPAG Cmax but not AcMPAG AUC, suggesting that only peak CSA concentrations on a low-dose CSA regimen are sufficient to impair the biliary excretion of AcMPAG. In summary, the influence of CSA on the exposure to MPA was attenuated in stable adult liver transplant recipients on a low-dose CNI therapy in combination with a fixed dose of MMF as compared with patients on a standard CNI therapy. Dose adjustment according to drug concentration measurements is recommended to optimize dosing of MMF and to maintain adequate immunosuppression in patients converted to low-dose CNI therapy.

show abstract

Section: Discussioncontrasting

confidence: 76%

Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolites in Stable Adult Liver Transplant Recipients With Renal Dysfunction on a Low-Dose Calcineurin Inhibitor Regimen and Mycophenolate Mofetil

Beckebaum¹,

Armstrong²,

Cicinnati³

et al. 2009

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

show abstract

“…18 However, several studies have reported that CyA affects the pharmacokinetics of MPA and MPAG. 15,[21][22][23] It remains to be clarified why the MPA AUC in LN patients was similar to that in KT recipients. In this study, the LN patient group had lower serum creatinine levels, higher doses of prednisolone, absence of CNI medication, and a higher proportion of women.…”

Section: Discussionmentioning

confidence: 97%

Comparison of Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Between Patients With Lupus Nephritis and With Kidney Transplantation

Mino

Naito²,

Matsushita³

et al. 2008

Therapeutic Drug Monitoring

Self Cite

View full text Add to dashboard Cite

The pharmacokinetics of mycophenolic acid (MPA) and its glucuronide (mycophenolic acid phenolic glucuronide, MPAG) in lupus nephritis (LN) have not been fully characterized. The aim of this study was to evaluate the pharmacokinetics of MPA and MPAG in LN patients by comparing the pharmacokinetics with those of kidney transplant (KT) recipients. Six LN patients (World Health Organization class IV and V) and 24 KT recipients [8 recipients treated with tacrolimus (Tac) and 16 with cyclosporine (CyA)] during the early posttransplantation period were enrolled. Pharmacokinetic parameters of MPA and MPAG were compared between LN patients and Tac-treated or CyA-treated KT recipients. The area under the concentration-time curve (AUC0-12) of MPA normalized to mycophenolate mofetil (MMF) dose (mg/kg) was significantly lower in LN patients and CyA-treated KT recipients than in Tac-treated KT recipients [median (range), 2.19 (0.87-4.23), 2.36 (1.13-5.74), and 4.86 (3.25-6.75) microg x h/mL per mg/kg, P < 0.05 and P < 0.01, respectively]. Dose-normalized MPAG AUC0-12 was significantly lower in LN patients and slightly lower in Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 35.0 (8.34-69.8), 51.6 (34.4-94.8), and 84.1 (34.7-152) microg x h/mL per mg/kg, P < 0.05 and P = 0.13, respectively]. The ratio of MPA AUC5-12 to AUC0-12, an estimate of MPA enterohepatic recirculation, was slightly higher in LN patients and Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 0.44 (0.35-0.56), 0.45 (0.42-0.61), and 0.34 (0.22-0.55), P = 0.29 and P = 0.10, respectively]. Serum creatinine was significantly lower in LN patients than in Tac-treated and CyA-treated KT recipients. In conclusion, the pharmacokinetics of MPA in LN patients is characterized by high MPA clearance and in CyA-treated KT recipients. Despite this higher clearance of MPA, MPAG AUC0-12 was lower in LN patients most likely due to better renal function in LN patients.

show abstract

“…In contrast to these studies demonstrating no or an inverse correlation between renal function and MPA exposure, other studies have associated renal impairment with higher MPA exposure (27)(28)(29)(30)(31)(32) (Table 1). The reason for these inconsistencies in the impact of renal function on MPA exposure is not clear.…”

mentioning

confidence: 85%

The Impact of Renal Allograft Function on Exposure and Elimination of Mycophenolic Acid (MPA) and Its Metabolite MPA 7-O-glucuronide

2007

View full text Add to dashboard Cite

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.

show abstract

Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

Cited by 46 publications

References 33 publications

Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolites in Stable Adult Liver Transplant Recipients With Renal Dysfunction on a Low-Dose Calcineurin Inhibitor Regimen and Mycophenolate Mofetil

Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolites in Stable Adult Liver Transplant Recipients With Renal Dysfunction on a Low-Dose Calcineurin Inhibitor Regimen and Mycophenolate Mofetil

Comparison of Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Between Patients With Lupus Nephritis and With Kidney Transplantation

The Impact of Renal Allograft Function on Exposure and Elimination of Mycophenolic Acid (MPA) and Its Metabolite MPA 7-O-glucuronide

Contact Info

Product

Resources

About