P6-17. Correlation between azathioprine metabolites concentrations and adverse events in patients with Inflammatory bowel disease

Kristina Pavlovska [1], Maja Slaninka Miceska [1], Emilija Atanasovska [1], Vladimir Avramovski [2], Vladimir Andreevski [2],Gjorgji Deriban [2], Jasmina Tonic Ribarska [3], Ljudmila Efremovska [4]
Affiliates: [1] Department of Preclinical and Clinical Pharmacology and Toxicology, Medical faculty, Skopje, Macedonia, [2] University Clinic of Gastroenterohepatology, Medical faculty, Skopje, Macedonia, [3] Faculty od Pharmacy, Skopje, [4] Institute of Physiology, Medical faculty,Skopje

Azathioprine (AZA) as an immunosuppressive drug is widely used in patients with Inflammatory bowel disease (IBD). Besides his proven efficacy, the main problem that remains during the treatment are the serious adverse events (AE’s) that can occur. The aim of this study was to investigate the correlation between azathioprine metabolite concentration and AE’s that were registered in patients (pts) with IBD.
Sixty- three IBD pts treated with AZA (>3 months) were included. A blood sample was taken (5mL) for determination of concentration of AZA metabolites:6-thioguanine nucleotides (6-TGN) and 6 methylmercaptopurine (6-MMP). High performance liquid chromatography method was used to determine the concentration of the metabolites. 6-TGN>450pmol/8×10(8)Er and 6-MMP>5700pmol/8×10(8)Er were considered as a criterion for toxicity. Pts were examined about the possible AE’s during AZA treatment.
The mean value of 6-TGN was 437,46 pmol/8×10(8)Er ± 198,82 pmol/8×10(8)Er (min. 64,8 pmol/8×10(8)Er, max. 905,5 pmol/8×10(8)Er) and for 6-MMP was 6497,87 pmol/8×10(8)Er ±7462,02 pmol/8×10(8)Er (min. 283,3 pmol/8×10(8)Er , max. 31324,4 pmol/8×10(8) Er).
Fifteen pts (24%) had AE’s (5 leukocytosis, 2 aphtous ulcer, 2 increased transaminases, 4 elevated amylase in serum, 2 polyarthralgia).
Analysis have shown that pts with AE’s had higher mean value of 6-TGN and 6-MMP, compared with pts without AE’s (6-TGN: 487,54 pmol/8×10(8)Er ± 185,57 pmol/8×10(8)Er v.s. 429,11 pmol/8×10(8)Er ± 203,39 pmol/8×10(8)Er ,p=0,5893 and 6-MMP: 7592,92 pmol/8×10(8)Er ±7534,19 pmol/8×10(8)Er v.s. 6295,08 pmol/8×10(8)Er ±7575,19 pmol/8×10(8)Er, p>0,05). 50% of the pts with AE’s had 6-TGN > 562,8 pmol/8×10(8)Er and 6-MMP>5877 pmol/8×10(8)Er, compared with 50% of pts without AE’s, where 6-TGN > 399,5 pmol/8×10(8)Er and 6-MMP>2891 pmol/8×10(8)Er.
Therapeutic monitoring of azathioprine metabolites could be a useful tool to predict the AE’s in patients with IBD. On the other hand, having the information for the metabolites, the dose of AZA can be adjusted.