PMID- 22486532
OWN - NLM
STAT- MEDLINE
DCOM- 20120628
LR  - 20171116
IS  - 1365-2036 (Electronic)
IS  - 0269-2813 (Linking)
VI  - 35
IP  - 10
DP  - 2012 May
TI  - High TPMT enzyme activity does not explain drug resistance due to preferential 
      6-methylmercaptopurine production in patients on thiopurine treatment.
PG  - 1181-9
LID - 10.1111/j.1365-2036.2012.05084.x [doi]
AB  - BACKGROUND: Up to 20% of patients on thiopurine therapy fail to achieve adequate 
      drug response. Many of these patients preferentially produce the toxic 
      6-methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine 
      nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased 
      risk of hepatotoxicity. AIM: To determine the prevalence of preferential 6-MMP 
      producers and define the relationships between 6-TGN, 6-MMP and thiopurine 
      methyltransferase (TPMT). METHODS: The database of 6-TGN, 6-MMP and TPMT 
      measurements from patients throughout New Zealand was used to calculate patients' 
      6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (</=20).The 
      TPMT enzyme activity was compared amongst the groups. RESULTS: Of 1879 patients 
      with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The 
      mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio 
      </=20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). 
      However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT 
      results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those 
      with 6-MMP/6-TGN ratio </=20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 
      IU/mL) vs. 7% in those with a ratio >20. CONCLUSIONS: In this patient population 
      with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP 
      producers. The results show that high TPMT enzyme activity is not the major 
      reason for preferential 6-MMP production in most patients with a high metabolite 
      ratio. This suggests that there are one or more important alternative mechanisms 
      for preferentially producing 6-MMP.
CI  - (c) 2012 Blackwell Publishing Ltd.
FAU - van Egmond, R
AU  - van Egmond R
AD  - Department of Clinical Pharmacology, Department of Gastroenterology, Christchurch 
      Hospital, New Zealand.
FAU - Chin, P
AU  - Chin P
FAU - Zhang, M
AU  - Zhang M
FAU - Sies, C W
AU  - Sies CW
FAU - Barclay, M L
AU  - Barclay ML
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120404
PL  - England
TA  - Aliment Pharmacol Ther
JT  - Alimentary pharmacology & therapeutics
JID - 8707234
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - 6V404DV25O (6-methylthiopurine)
RN  - E7WED276I5 (Mercaptopurine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - FTK8U1GZNX (Thioguanine)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
CIN - Aliment Pharmacol Ther. 2012 Jul;36(2):208-9; author reply 209-10. PMID: 22703467
MH  - Antimetabolites, Antineoplastic/*therapeutic use
MH  - Azathioprine/*therapeutic use
MH  - Chromatography, High Pressure Liquid
MH  - Drug Resistance
MH  - Erythrocyte Membrane/metabolism
MH  - Female
MH  - Genotype
MH  - Guanine Nucleotides/*blood
MH  - Humans
MH  - Inflammatory Bowel Diseases/blood/drug therapy/*enzymology
MH  - Male
MH  - Mercaptopurine/*analogs & derivatives/blood
MH  - Methyltransferases/*blood/genetics
MH  - Statistics as Topic
MH  - Thioguanine/*therapeutic use
MH  - Thionucleotides/*blood
EDAT- 2012/04/11 06:00
MHDA- 2012/06/29 06:00
CRDT- 2012/04/11 06:00
PHST- 2011/11/10 00:00 [received]
PHST- 2011/12/07 00:00 [revised]
PHST- 2012/02/29 00:00 [revised]
PHST- 2012/03/13 00:00 [accepted]
PHST- 2012/04/11 06:00 [entrez]
PHST- 2012/04/11 06:00 [pubmed]
PHST- 2012/06/29 06:00 [medline]
AID - 10.1111/j.1365-2036.2012.05084.x [doi]
PST - ppublish
SO  - Aliment Pharmacol Ther. 2012 May;35(10):1181-9. doi: 
      10.1111/j.1365-2036.2012.05084.x. Epub 2012 Apr 4.