Dr Sharon Rees @reesprescribe
Day 1: A metabolite of azathioprine, #mercaptopurine was discovered to be an immunosuppressant circa 1950s. The role for #mercaptopurine developed in leukaemias (acute and maintenance therapy) and inflammatory bowel disease (IBD) for maintenance of remission for Crohn's disease and ulcerative colitis (IBD unlicensed role).
Dr Sharon Rees @reesprescribe
(cont) Dose; significant individual variations in kinetics such as drug metabolism, and in dynamics such as intracellular uptake and breakdown, mean an individual approach. Adult acute chemotherapy 2.5-5 mg/kg PO once daily, maintenance 1.5-2.5 mg/kg/day. IBD 1-1.5 mg/kg; British National Formulary states lower can be effective e.g some IBD sites state 0.75-1.5 mg/kg/day. Use unlicensed in children, chemotherapy dose customised, IBD as per adult.
Dr Sharon Rees @reesprescribe
Day 2: #mercaptopurine is a purine analogue, which competes with purines for enzymatic breakdown at multiple stages, interfering with nucleic acid synthesis. Acting as a purine decoy impairs DNA formation with toxic breakdown products, leading to cell death.
Dr Sharon Rees @reesprescribe
(cont) Rapidly dividing cells such as tumours and bone marrow blood cells are most affected, some of which control inflammation. When used in inflammatory bowel conditions, the effects/full effects may not be experienced for three, or even six months.
Dr Sharon Rees @reesprescribe
Day 3: Key kinetics; oral bioavailability is variable and affected by some food (drug is taken 1-hour before or 2 hours after milk/dairy products).
Dr Sharon Rees @reesprescribe
(cont) There is extensive metabolism by multiple pathways. Polymorphisms are relevant as they can predict adverse drug reactions such as TPMT defficiency. Elimination is triphasic; t ½ at 45 mins, 2.5-hours and 10-hours.
Dr Sharon Rees @reesprescribe
Day 4: The toxic compounds formed from cell uptake of #mercaptopurine are broken down to non-toxic metabolites by enzymes such as TPMT, which is subject to genetic polymorphisms. TPMT testing is recommended before starting. Less than 1% of the population have TMPT defficiency (use alternative drug), but up to 11% have reduced levels, which still increases the risk of toxicity (lower dose).
Dr Sharon Rees @reesprescribe
Day 5: ADRs; Common – nausea, diarrhoea, leucopenia, thrombocytopenia, appetite reduced. Serious – bone marrow suppression, hepatotoxicity, pancreatitis (not exhaustive). Regular haematology monitoring and LFTs important. #mercaptopurine may increase the risk of non-melanoma skin cancer; ADVISE re UV light protection.
Dr Sharon Rees @reesprescribe
Day 6: DDIs; Many common drugs increase risk of hepatotoxicity such as flucloxacillin, statins, valproate. Monitor INR with warfarin. Xanthine oxidase breaks down #mercaptopurine, so gout drugs eg allopurinol and febuxostat can increase risk toxicity. If combined, reduce #mercaptopurine dose by 25%.
Dr Sharon Rees @reesprescribe
Day 7: Interesting fact. Dairy avoidance (1 hour before or 2 hours after dairy) is recommended because cow's milk is high in xanthine oxidase which starts to break down the drug, making less bioavailable.