Mercaptopurine drug interactions

There are several important drug-drug interactions with allopurinol. The effects of both theophylline and warfarin may be potentiated by allopurinol. Azathioprine and 6-mercaptopurine are purines whose metabolism is inhibited... 

Oral allopurinol (Zyloprim ) Adult 600-800 mg/day in 2-3 divided doses Child 10 mg/kg per day or 200-300 mg/m2 per day Adult 200-400 mg/m2 per day Child 200 mg/m2 per day 0.48/day (generic) Adjust dose for renal impairment. Avoid drug interactions (mercaptopurine). Monitor for skin rash. 

Andersen JB, Szumlanski C, Weinshilboum RM et al. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 1998 87 108-111. 

Lewis LD, Benin A, Szumlanski C. Olsalazine and 6-mercaptopurine-related hematologic suppression a possible drug-drug interaction. Clin Pharmacol Ther 1997 62 464-475. 

Lowry PW, Franklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV, Tremaine WJ, Lipsky JJ, Weinshilboum RM, Sandborn WJ. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or bal-salazide. Gut 2001 49(5) 656-64. 

Fernandez MA, Regadera A, Aznar J. Acenocoumarol and 6-mercaptopurine an important drug interaction. Haematologica 1999 84(7) 664-5. 

Spiers AS, Mibashan RS. Letter Increased warfarin requirement during mercaptopurine therapy a new drug interaction. Lancet 1974 2(7874) 221-2. 

Toxicity and drug interactions Like uricosuric drugs, allopurinol can precipitate acute attacks of gout during the early phase of treatment. Allopurinol causes gastrointestinal upset and, rarely, peripheral neuritis and vasculitis. Allopurinol inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend upon xanthine oxidase for elimination. 

Allopurinol, a xanthine oxidase inhibitor used for the treatment of gout, inhibits metabolism of 6-mercaptopurine and other drugs metabolized by this enzyme. A serious drug interaction results from the concurrent use of allopurinol for gout and 6-mercaptopurine to block the immune response from a tissue transplant or as antimetabolite in neoplastic diseases. In some cases, however, allopurinol is used in conjunction with 6-mercaptopurine to control the increase in uric acid elimination from 6-mercaptopurine metabolism. The patient should be supervised closely, because when given in large doses, allopurinol, an inhibitor of purine metabolism, may have serious effects on bone marrow. 

Lowry PW, Szumlanski CL, Weinshilboum RM, Sandbom WJ. Balsalazide and azathioprine or 6-mercaptopurine evidence for a potentially serious drug interaction. Gastroenterology... 

Drug-drug interactions Azathioprine/6-mercaptopurine The association between mesalazine and the induction of myelotoxicity by thiopurine therapy in patients with inflammatory bowel disease was investigated by using both retrospective and prospective studies. Of the 139 patients included in ffie retrospective observational study, 45 were on azathioprine/6-mercaptopurine plus mesalazine, while 94 were on azatiiioprine/6-mercaptopurine alone. The dose of azathioprine in the retrospective study was 2 mg/kg/day, while ffie dose of 6-mercaptopurine was 1 mg/kg/day. Their myelotoxicity rates were 47% and 16%, respectively. Multivariate regression analysis indicated that concomitant mesalazine was the only risk factor associated with myelotoxicity (odds ratio 3.45,95% confidence interval 1.31-9.04, P = 0.01). The prospective study was performed in 16 patients with active disease, treated with azathioprine (50 mg/ day) for 4 weeks followed by concomitant mesalazine (3 g/day) for additional 4 weeks. After 4 weeks on azathioprine no patient developed myelotoxicity. However, after an additional 4 weeks with concomitant mesalazine, two patients developed myelotoxicity. Overall, it appears that the risk of thiopurine-induced myelotoxicity is markedly increased in patients treated with combined mesalazine and 2 mg/kg/day azathioprine. Azathioprine (50 mg, daily) with concomitant mesalazine might help to maintain efficacy without increasing the risk of myelotoxicity [80 ]. 

Azathioprine is a pro-drug as it is converted by interaction, mainly in red blood cells, with nucleophils like glutathione to its active form 6-mercaptopurine after which 6-mercaptopurine nucleotides are generated that inhibit purine synthesis and can lead to DNA damage by intercalation. Although the activity of 6-mercaptopurine is well understood there are indications that azathioprine itself contributes to an enhanced immunosuppressive activity. 

Mercaptopurine ribonucleotide is an important drug that inhibits various nucleotide-metabolizing enzymes (71). With adenylosuccinate synthetase from mammalian sources, inhibition by 6-mercaptopurine ribonucleotide appears to be similar to AMP, interacting with both nucleotide substrate sites. KiS of 44-55 fiM have been reported (45). With the bacterial enzymes, somewhat lower A iS have been observed, 10-25 fj-M, and the inhibition appears to be generally competitive with respect to IMP only (9,14). 

The nature of the enhancement of antibody production by 3-butylazathioprine has not been established. Enhancement has been obtained in animals pretreated with 6-mercaptopurine and other commonly used immunosuppressive drugs (Schwartz, 1965). Schwartz proposed that the cytotoxic drugs resulted in cell damage with subsequent release of stimulatory polynucleotides. The observed effects of 3-butylazathioprine could be such an indirect result of cytotoxicity or alternatively may reflect a direct interaction of the drug with cells involved in the immune response. 

Drug-drug interactious Methotrexate The pharmacokinetic interaction between methotrexate and mercaptopurine has been studied in 20 children with acute lymphoblastic leukemia [154 ]. High-dose methotrexate (5 g/m over 24 hours) produced a rapid reduction in erythrocyte concentrations of thioguanine within 24 hours, and... 

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