Disappearance of measurable mycophenolate mofetil (Cell Cept®) in a patient with a renal transplant and an ileostomy

Lasse Gunnar Gøransson and Harald Bergrem

Department of Medicine, Renal Unit, Central Hospital of Rogaland, Stavanger, Norway

Sir,

Mycophenolate mofetil is a potent, uncompetitive, reversible inhibitor of eukaryotic inosine monophosphate dehydrogenase. It is effective in the suppression of acute allograft rejection following cadaveric renal transplantation when given orally twice daily in combination with cyclosporin and steroids [1]. Its clinical pharmacology, including its intestinal absorption characteristics, has been reviewed [2]. We present here the first reported case of the effect of an ileostomy on mycophenolate mofetil disposition.

Case.

We present the case of a 50-year-old woman who developed end-stage renal failure due to polycystic kidney disease and started haemodialysis in July 1999. She received a living donor kidney from her sister in January 2000. Her immunosuppressive medication included prednisolone, mycophenolate mofetil (Cell Cept®) and tacrolimus (Prograf®). Four months after the transplantation, she had a rectal bleeding, and a diagnostic colonoscopy was performed. Colon diverticula were found in colon sigmoideum and rectum. The procedure was complicated by a perforation and, after demonstration of free air on a plain abdominal X-ray, the patient had an explorative laparatomy, showing a dilated colon. No perforation or intra-abdominal infection was found, and a temporary ileostomy at the level of the terminal ileum was performed. Post-operatively, the patient developed a profuse, watery, diarrhoea resulting in dehydration and weight loss, and a transient increase in serum creatinine level. She was treated with intravenous saline three times weekly on an out-patient basis. Her immunosuppressive treatment was left unchanged. Seven weeks later, the ileostomy was closed, resulting in normalization of bowel action, and stabilization of body weight and serum creatinine. The serum levels of tacrolimus and mychophenolic acid were measured pre-operatively, twice during the ileostomy period, and after the ileostomy was closed. The mychophenolic acid levels during the period with an ileostomy were undetectable, whereas the tacrolimus levels were almost identical to the pre-operative levels (Table 1Go). At follow-up 3 weeks after closure of the ileostomy, the mycophenolic acid level had returned to a level almost identical to that pre-operatively.


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Table 1. Laboratory values

 

Discussion.

After oral administration, mycophenolate mofetil is rapidly and completely converted to the active mycophenolic acid, and the mycophenolate mofetil concentration in plasma is not quantifiable [2]. Mycophenolic acid is metabolized in the liver to mycophenolic acid glucoronide which is excreted in the urine and bile [3], and undergoes an enterohepatic recirculation as indicated by a secondary peak in mycophenolic acid plasma concentration after 6–12 h [2]. Mycophenolic acid glucoronide is probably deglucoronidated in the colon to mycophenolic acid mediated by the gut flora [4]. The dramatic fall in mycophenolic acid concentration in our patient was probably due to interruption of the enterohepatic recirculation of the drug due to the ileostomy and profuse diarrhoea. Tacrolimus is almost completely metabolized by the liver and no enterohepatic recirculation is reported [5]. We have no reason to suspect poor compliance with medication as a possible cause. Our transplant recipients routinely keep daily records of their body weight, temperature and tablet intake, and the records are presented at follow-up visits.

Conclusion.

In patients with profuse diarrhoea and/or an ileostomy, the mycophenolic acid concentration in plasma should be monitored intensively.

References

  1. Sollinger H. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation1995; 60: 225–232[ISI][Medline]
  2. Bullingham R, Monroe S, Nicholls A, Hale M. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose and intravenous administration. J Clin Pharmacol1996; 36: 315–324[Abstract/Free Full Text]
  3. Bardsley-Elliot A, Noble S, Foster RH. Mycophenolate mofetil. A review of its use in the management of solid organ transplantation. Biodrugs1999; 12: 363–410[ISI]
  4. Bullingham RES, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet1998; 34: 429–455[ISI][Medline]
  5. Venkataramanan R, Jain A, Cadoff E et al. Pharmacokinetics of FK 506: preclinical and clinical studies. Transplant Proc1990; 22 [Suppl 1]: 52–56[ISI][Medline]




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