PMID- 37218386
OWN - NLM
STAT- MEDLINE
DCOM- 20230721
LR  - 20230725
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 89
IP  - 8
DP  - 2023 Aug
TI  - Azathioprine-induced vanishing bile duct syndrome: The value of early thiopurine 
      metabolism assessment.
PG  - 2625-2630
LID - 10.1111/bcp.15797 [doi]
AB  - About 15% to 28% of patients treated with thiopurines experienced adverse drug 
      reactions, such as haematological and hepatic toxicities. Some of these related 
      to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key 
      detoxifying enzyme of thiopurine metabolism. We report here a case of 
      thiopurine-induced ductopenia with a comprehensive pharmacological analysis on 
      thiopurine metabolism. A 34-year-old woman, with a medical history of severe 
      systemic lupus erythematosus with recent introduction of azathioprine therapy, 
      presented with mild fluctuating transaminase blood levels consistent with a 
      hepatocellular pattern, which evolved to a cholestatic pattern over the next 
      weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides 
      (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides 
      (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and 
      a high TPMT activity. After a total of about 6 months of thiopurine therapy, a 
      transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation 
      led to further clinical improvement. In line with previous reports from the 
      literature, our case supports the fact that ductopenia is a rare adverse drug 
      reaction of azathioprine. The mechanism of reaction is unknown but may involve 
      high 6-MMPN blood level, due to unusual thiopurine metabolism (switched 
      metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 
      6-MMPN blood levels may help physicians to identify patients at risk of similar 
      duct injury.
CI  - (c) 2023 The Authors. British Journal of Clinical Pharmacology published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Chouchana, Laurent
AU  - Chouchana L
AUID- ORCID: 0000-0002-9626-3571
AD  - Centre Regional de Pharmacovigilance, Service de Pharmacologie perinatale, 
      pediatrique et adulte, Hopital Cochin, AP-HP.Centre, Universite Paris Cite, 
      Paris, France.
FAU - Terris, Benoit
AU  - Terris B
AUID- ORCID: 0000-0002-3571-7277
AD  - Service de Pathologie, Hopital Cochin, AP-HP.Centre, Universite Paris Cite, 
      Paris, France.
FAU - Sogni, Philippe
AU  - Sogni P
AUID- ORCID: 0000-0003-3316-8785
AD  - Service d'hepatologie, Hopital Cochin, AP-HP.Centre, Universite Paris Cite, 
      Paris, France.
FAU - Treluyer, Jean-Marc
AU  - Treluyer JM
AUID- ORCID: 0000-0002-2045-4742
AD  - Centre Regional de Pharmacovigilance, Service de Pharmacologie perinatale, 
      pediatrique et adulte, Hopital Cochin, AP-HP.Centre, Universite Paris Cite, 
      Paris, France.
FAU - Costedoat-Chalumeau, Nathalie
AU  - Costedoat-Chalumeau N
AUID- ORCID: 0000-0001-6031-574X
AD  - Centre de reference maladies auto-immunes et systemiques rares d'Ile de France, 
      Departement de Medecine interne, Hopital Cochin, AP-HP.Centre, Universite Paris 
      Cite, Paris, France.
AD  - INSERM U 1153, Center for Epidemiology and Statistics Sorbonne Paris Cite 
      (CRESS), Paris, France.
FAU - Loriot, Marie-Anne
AU  - Loriot MA
AUID- ORCID: 0000-0001-9102-2667
AD  - Unite de Pharmacogenetique, Service de Biochimie, Hopital europeen Georges 
      Pompidou, AP-HP.Centre, Universite Paris Cite, Paris, France.
AD  - INSERM U1147, Medecine Personnalisee Pharmacogenomique et Optimisation 
      Therapeutique (MEPPOT), Paris, France.
LA  - eng
PT  - Case Reports
DEP - 20230606
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - MRK240IY2L (Azathioprine)
RN  - 0 (Immunosuppressive Agents)
RN  - FTK8U1GZNX (Thioguanine)
RN  - 0 (Thionucleotides)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - E7WED276I5 (Mercaptopurine)
RN  - 0 (Guanine Nucleotides)
SB  - IM
MH  - Female
MH  - Humans
MH  - Adult
MH  - *Azathioprine/adverse effects
MH  - Immunosuppressive Agents
MH  - Thioguanine/metabolism
MH  - *Lupus Erythematosus, Systemic/drug therapy
MH  - Thionucleotides
MH  - Methyltransferases/metabolism
MH  - Bile Ducts/metabolism
MH  - Mercaptopurine/therapeutic use
MH  - Guanine Nucleotides/metabolism
OTO - NOTNLM
OT  - ductopenia
OT  - hepatitis
OT  - pharmacogenomics
OT  - pharmacovigilance
OT  - thiopurine
OT  - vanishing bile duct syndrome
EDAT- 2023/05/23 06:42
MHDA- 2023/07/21 06:42
CRDT- 2023/05/23 03:46
PHST- 2023/05/13 00:00 [revised]
PHST- 2023/03/03 00:00 [received]
PHST- 2023/05/17 00:00 [accepted]
PHST- 2023/07/21 06:42 [medline]
PHST- 2023/05/23 06:42 [pubmed]
PHST- 2023/05/23 03:46 [entrez]
AID - 10.1111/bcp.15797 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2023 Aug;89(8):2625-2630. doi: 10.1111/bcp.15797. Epub 2023 
      Jun 6.