Variability of Mycophenolate Mofetil Trough Levels in Stable Kidney Transplant Patients

Fernandez, Armida; Martins, Judith; Villlafruela, J.J.; Marcén, R.; Pascual, Julio; Cano, Teresa Rodríguez; Puig, C.; Gil-Casares, Beatriz; Muriel, Alfonso; Burgos, Francisco; Ortuño, J

doi:10.1016/j.transproceed.2007.06.025

Cited by 8 publications

(7 citation statements)

References 11 publications

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“…Because lymphocytes rely on de novo synthesis to provide guanine nucleotides while most other cells use the salvage pathway, inhibition of IMPDH results in immunosuppression (Allison and Eugui, 2000). However, in addition to having a narrow therapeutic index, clinical response to MPA is quite variable, and is complicated by large individual variation in both MPA plasma concentrations (Pisupati et al ., 2005; Fernandez et al ., 2007) and levels of IMPDH activity (Glander et al ., 2001; 2004).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics

Peng

Pelleymounter

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSEInosine monophosphate dehydrogenases, encoded by IMPDH1 and IMPDH2, are targets for the important immunosuppressive drug, mycophenolic acid (MPA). Variation in MPA response may result, in part, from genetic variation in IMPDH1 and IMPDH2. EXPERIMENTAL APPROACHWe resequenced IMPDH1 and IMPDH2 using DNA from 288 individuals from three ethnic groups and performed functional genomic studies of the sequence variants observed. KEY RESULTSWe identified 73 single nucleotide polymorphisms (SNPs) in IMPDH1, 59 novel, and 25 SNPs, 24 novel, in IMPDH2. One novel IMPDH1 allozyme (Leu275) had 10.2% of the wild-type activity as a result of accelerated protein degradation. Decreased activity of the previously reported IMPDH2 Phe263 allozyme was primarily due to decreased protein quantity, also with accelerated degradation. These observations with regard to the functional implications of variant allozymes were supported by the IMPDH1 and IMPDH2 X-ray crystal structures. A novel IMPDH2 intron 1 SNP, G > C IVS1(93), was associated with decreased mRNA quantity, possibly because of altered transcription. CONCLUSIONS AND IMPLICATIONSThese results provide insight into the nature and extent of sequence variation in the IMPDH1 and IMPDH2 genes. They also describe the influence of gene sequence variation that alters the encoded amino acids on IMPDH function and provide a foundation for future translational studies designed to correlate sequence variation in these genes with outcomes in patients treated with MPA.

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Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics

Peng

Pelleymounter

et al. 2010

British J Pharmacology

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“…As substantial and largely unexplained intraindividual variability of mycophenolate mofetil pharmacokinetics has been described, 18,19 other factors contributing to the decrease in MPA concentrations cannot be excluded. Of note, after ciprofloxacin was discontinued on day 15, PHARMACOTHERAPY Volume 31, Number 1, 2011 40e MPA concentrations never achieved the level measured the day before ciprofloxacin was started on day 8, despite significant mycophenolate mofetil dosage increases.…”

Section: Discussionmentioning

confidence: 99%

Probable Drug Interaction Between Intravenous Ciprofloxacin and Mycophenolate Mofetil in a Bone Marrow Transplant Recipient

Goutelle¹,

Mialou²,

Gouraud³

et al. 2011

Pharmacotherapy

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Several studies have reported that oral antibacterials, including ciprofloxacin, administered during mycophenolate mofetil therapy may reduce mycophenolic acid (the active drug moiety) exposure. To our knowledge, however, this effect has never been described with antibiotics administered by the parenteral route. We describe a 17‐year‐old female who received intravenous mycophenolate mofetil after bone marrow transplantation, with therapeutic drug monitoring performed during therapy. On day 2 of mycophenolate mofetil therapy, the mycophenolic acid area under the plasma concentration‐time curve was 30.3 mg•hour/L. On day 8, although her mycophenolate mofetil dosage had remained unchanged, the mycophenolic acid area under the plasma concentration‐time curve was unexpectedly lower at 10.7 mg•hour/L. A drug interaction was suspected. Three intravenous antiinfective drugs had been introduced after initial therapeutic drug monitoring had been performed—ciprofloxacin, trimethoprim‐sulfamethoxazole, and caspofungin. The patient subsequently developed severe graft‐versus‐host disease during mycophenolate mofetil therapy and died. Use of the Horn drug interaction probability scale indicated a probable interaction between intravenous mycophenolate mofetil and intravenous ciprofloxacin in this patient. The available literature does not support the role of either trimethoprim‐sulfamethoxazole or caspofungin in a drug interaction with mycophenolate mofetil. Published studies have shown that ciprofloxacin is partially excreted by transintestinal elimination after intravenous administration and that it may greatly reduce the levels of enterobacteria of gastrointestinal flora, which are responsible for mycophenolic acid enterohepatic recirculation. Clinicians should be aware that ciprofloxacin, even administered intravenously, may modify the pharmacokinetics of mycophenolate mofetil. Ciprofloxacin should be used with caution in patients receiving mycophenolate mofetil; if this antiinfective must be used, therapeutic drug monitoring should be performed to guide dosage adjustments.

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“…27) Large intraindividual variation in MPA C 0 was also associated with poor renal function and proteinuria. 28) In this study, the enrolled kidney transplant recipients had stable renal function (serum creatinine concentration not exceeding 3 mg/dl) and had been receiving an unchanged immunosuppressant regimen for at least two months. We believe that consideration of the contribution of EHR to total MPA exposure and stratified analysis based on the CNI treatment were needed for evaluation of the pharmacokinetic interaction between MMF and concomitant MCs.…”

Section: Discussionmentioning

confidence: 99%

Influence of Metal Cations on Plasma Trough Concentration of Mycophenolic Acid and Its Glucuronide in Tacrolimus-Treated and Cyclosporine-Treated Kidney Transplant Recipients

Naito

Mino

Otsuka

et al. 2008

Biological & Pharmaceutical Bulletin

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Mycophenolic acid (MPA), an active component of the prodrug mycophenolate mofetil (MMF), is an immunosuppressant, which effectively prevents rejection after kidney transplantation.1) MPA is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) at the phenolic hydroxyl group to form the inactive metabolite MPA 7-Oglucuronide (MPAG), which mainly undergoes urinary excretion. In triple immunosuppressive regimens including MMF, calcineurin inhibitors (CNIs), and glucocorticoids, concomitant CNIs cause pharmacokinetic interactions with MPA and MPAG. [2][3][4][5][6] An example of such interactions is the inhibition of the biliary excretion of MPAG by cyclosporine (CyA). 7,8) MMF and MPA contain 4-hydroxy radical and 3-oxo-benzofuran groups that may be involved in the formation of a chelate complex with a divalent or trivalent metal cation (MC). However, the pharmacokinetic interactions between MMF and concomitant MCs have not been fully characterized in clinical practice.The authors experienced the opportunity to co-administer MCs with MMF in kidney transplant recipients. Iron deficiency and secondary hyperparathyroidism are often observed in stable kidney transplant recipients.9) Kidney transplant recipients who undergo parathyroidectomy can develop hypocalcemia that requires treatment with calcium preparations. As previously reported, oral administration of ferrous sulfate decreased MMF intestinal absorption to 10% in healthy subjects.10) There was a 50% reduction in MMF intestinal absorption when calcium polycarbophil was co-administered with MMF in healthy subjects.11) However, recent reports have demonstrated that MPA pharmacokinetics was unchanged in kidney transplant patients treated with a combination of iron preparations and MMF. [12][13][14] On the other hand, antacid containing aluminum hydroxide and magnesium oxide reduced MPA and MPAG exposure in rheumatoid arthritis patients. 15)MPAG undergoes enterohepatic recirculation (EHR) and its contribution to total MPA exposure is 10-60% in humans.16) There is clinical evidence indicating that inhibition of EHR by CyA could explain the differences observed in MPA pharmacokinetics when co-administered with either Tac or CyA.17) The aim of this study was to evaluate the MPA C 0 and MPAG C 0 as well as the ratio of MPAG to MPA between MC(Ϫ) (non-treated) and MC(ϩ) (co-treated) patients in a stratified analysis based on CNI treatment. MATERIALS AND METHODS EthicsThis study was performed in accordance with the Declaration of Helsinki and its amendments, and its protocol was approved by The Ethics Committee of Hamamatsu University Hospital. Each patient received information about the scientific aim of the study and each provided written informed consent.Patients and Study Schedule A total of 59 Japanese kidney transplant recipients receiving an immunosuppressive regimen containing CNIs and MMF (CellCept ® , Chugai Pharmaceutical, Tokyo) more than 3 months post-transplantation at Hamamatsu University Hospital was included in the study (Table 1)

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Variability of Mycophenolate Mofetil Trough Levels in Stable Kidney Transplant Patients

Cited by 8 publications

References 11 publications

Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics

Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics

Probable Drug Interaction Between Intravenous Ciprofloxacin and Mycophenolate Mofetil in a Bone Marrow Transplant Recipient

Influence of Metal Cations on Plasma Trough Concentration of Mycophenolic Acid and Its Glucuronide in Tacrolimus-Treated and Cyclosporine-Treated Kidney Transplant Recipients

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