title: High TPMT enzyme activity does not explain drug resistance due to preferential 6-methylmercaptopurine production in patients on thiopurine treatment.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology, Department of Gastroenterology, Christchurch Hospital, New Zealand.
authors.forename: R
authors.initials: R
authors.lastname: van Egmond
authors.forename: P
authors.initials: P
authors.lastname: Chin
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: C W
authors.initials: CW
authors.lastname: Sies
authors.forename: M L
authors.initials: ML
authors.lastname: Barclay
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001379:Azathioprine / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004351:Drug Resistance; D004910:Erythrocyte Membrane / Q000378:metabolism; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000097:blood; D008780:Methyltransferases / Q000097:blood* / Q000235:genetics; D013223:Statistics as Topic; D013866:Thioguanine / Q000627:therapeutic use*; D013873:Thionucleotides / Q000097:blood*
chemical_list: D000964:Antimetabolites, Antineoplastic; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine