Summary

DOI: 10.1373/clinchem.2012.195750

A 24-year-old woman (53 kg) with a 5-year history of steroid-dependent ulcerative colitis with mild and extensive ulcerations presented to the gastroenterology clinic for symptom recurrence. She was given 100 mg/day (1.9 mg · kg−1 · day−1) azathioprine (AZA)5 for 1 month, after which the dose was increased to 125 mg/day (2.3 mg · kg−1 · day−1).


Student Discussion

Student Discussion Document (pdf)

Laurent Chouchana,1,2,3 Denis Roche,1 Raymond Jian,2,4 Philippe Beaune,1,2,3 and Marie-Anne Loriot1,2,3*

1Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Biochimie, Pharmacogénétique et Oncologie Moléculaire, Paris, France; 2Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 3INSERM UMRS775, Paris, France; 4Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hepato-gastroenterologie et endoscopie digestive, Paris, France.
*Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Biochimie, Pharmacogénétique et Oncologie Moléculaire, 20 rue Leblanc, Paris, France. Fax: +33-1-56-09-33-93; E-mail: [email protected]

Case Description

A 24-year-old woman (53 kg) with a 5-year history of steroid-dependent ulcerative colitis with mild and extensive ulcerations presented to the gastroenterology clinic for symptom recurrence. She was given 100 mg/day (1.9 mg · kg-1 · day-1) azathioprine (AZA) for 1 month, after which the dose was increased to 125 mg/day (2.3 mg · kg-1 · day-1). Four months later, the patient was tapered off steroid therapy. Her symptoms persisted after 7 months of AZA therapy, however, and she experienced gastrointestinal side effects. The patient was switched to another thiopurine drug, 6-mercaptopurine (6-MP), at 75 mg/day (1.4 mg · kg-1 · day-1), which was well tolerated but similarly ineffective (8 stools daily). A brief course of steroid therapy rapidly produced a substantial but short-lived clinical improvement.

To understand this patient’s unresponsiveness to 2 thiopurine agents, we quantified thiopurine metabolites (1) 1 year after initiating AZA therapy. Intraerythrocyte concentrations of 6-thioguanine nucleotides (6-TGNs) were low (132 pmol/8 · 108 erythrocytes; therapeutic interval, 230–400 pmol/8 · 108 erythrocytes), and 6- methylmercaptopurine ribonucleotides (6-MMPRs) were very high (11 666 pmol/8 · 108 erythrocytes; therapeutic interval, <5800 pmol/8 · 108 erythrocytes). A second quantification of thiopurine metabolites 3 months later confirmed these results (6-TGNs, 127 pmol/8 · 108 erythrocytes; 6-MMPR, 26 304 pmol/8 · 108 erythrocytes). The patient had an unusual and extremely high thiopurine S-methyltransferase (TPMT) activity in erythrocytes [61.5 nmol · h-1 · (mL erythrocytes)-1; reference interval, 8.5–15 nmol · h-1 · (mL erythrocytes)-1]. The lack of clinical efficacy for 6-MP, together with the evidence of pharmacologic resistance, prompted discontinuation of 6-MP therapy. Thereafter, we administered the tumor necrosis factor-α (TNF-α) antagonist adalimumab, but we quickly replaced it with infliximab, which has a good clinical efficacy and safety profile.

Reference

  1. Dervieux T, Boulieu R. Simultaneous determination of 6-thioguanine and methyl 6- mercaptopurine nucleotides of azathioprine in red blood cells by HPLC. Clin Chem 1998;44: 551–5.

Questions to Consider

  • What is the clinical utility of assessing the TPMT phenotype or genotype?
  • What is the rationale for therapeutic drug monitoring of thiopurines?
  • What causes of resistance should be considered before switching to another drug class in patients with apparent thiopurine resistance?
  • How can thiopurine treatment be optimized in patients with a very high TPMT activity?

Final Publication and Comments

The final published version with discussion and comments from the experts appears in the July 2013 issue of Clinical Chemistry, approximately 3-4 weeks after the Student Discussion is posted.

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DOI: 10.1373/clinchem.2012.195750
Copyright © 2013 American Association for Clinical Chemistry