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 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;
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
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.
- 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:
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
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