White cell azathioprine metabolites for patients on thiopurines
Research type
Research Study
Full title
The establishment of a new generation azathioprine metabolite monitoring test based on white cells.
IRAS ID
128241
Contact name
Simon McLaughlin
Contact email
Sponsor organisation
The Royal Bournemouth Hospital and Christchurch Hospital NHS Foundation Trust
Research summary
Summary of Results
Background:
The use of azathioprine for inflammatory bowel disease is limited by side effects or not controlling the disease. Combining azathioprine at a lower dose with another drug (allopurinol) is known to bypass many side effects and improves the chance of controlling IBD, and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine and low dose treatment combined with allopurinol work by similar mechanisms, using incorporation of the drug active breakdown product (deoxythioguanosine) into patient DNA, white-blood cell counts, and transcriptome analysis as biological markers of drug effect.Results:
There were no differences in reduction of white-cell counts between the 2 treatment groups, but patients on low dose azathioprine and allopurinol had lower DNA-incorporated drug active breakdown product (deoxythioguanosine) than those on standard dose azathioprine; for both groups, incorporated drug active breakdown product (deoxythioguanosine) was lower in patients on treatment for 24 weeks or more (maintenance of remission) compared to patients treated for less than 24 weeks (achievement of remission). Patients on combined low dose azathioprine and allopurinol had higher levels of the active drug metabolite (thioguanine nucleotides) in their red-blood cells than those on standard dose azathioprine, but there was no correlation between these or the waste product (methylated metabolites) that is thought to cause side effects, and incorporated deoxythioguanosine. Analysis of the DNA suggested down-regulation of immune responses consistent with effective immunosuppression in patients receiving low dose azathioprine and allopurinol, with evidence for different mechanisms of action between the 2 therapies.Conclusions:
Low dose azathioprine and allopurinol is effective despite lower amounts of its active breakdown product being added into DNA, and has different mechanisms of action compared to standard-dose azathioprine.REC name
South West - Cornwall & Plymouth Research Ethics Committee
REC reference
13/SW/0093
Date of REC Opinion
18 Apr 2013
REC opinion
Further Information Favourable Opinion