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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.
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.

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  • Publisher Full Text

    • Authors

    van Egmond R, Chin P, Zhang M, Sies CW, Barclay ML

    Institution

    Department of Clinical Pharmacology, Department of Gastroenterology, Christchurch Hospital, New Zealand.

    Source

    Alimentary pharmacology & therapeutics 35:10 2012 May pg 1181-9

    MeSH

    6-Mercaptopurine
    Antimetabolites, Antineoplastic
    Azathioprine
    Chromatography, High Pressure Liquid
    Drug Resistance
    Erythrocyte Membrane
    Female
    Genotype
    Guanine Nucleotides
    Humans
    Inflammatory Bowel Diseases
    Male
    Methyltransferases
    Statistics as Topic
    Thioguanine
    Thionucleotides

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22486532