Mercaptopurine interaction

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. 

Mercaptopurine [6-MP] (Purinethol) [Antineoplastic/ Antimeta lite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypoxanthine Dose Adults. 80-100 mg/mVd or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol X w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice. Hep Interactions T Effects W/ allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole X effects OF warfarin EMS May falsely T glucose OD May cause NA and liver necrosis symptomatic and supportive Meropenem (Merrem) [Antibiotic/Carbapenem] Uses lntra-abd Infxns, bacterial meningitis Action Carbapenem X cell wall synth, a [3-lactam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h in renal insuff Caution [B, ] Contra [3-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

Uses AML, ALL, CML Action Purine-based antimetabolite (substitutes for natural purines interfering w/ nucleotide synth) Dose 2-3 mg/kg/d X in severe renal/hepatic impair Caution [D, -] Contra Resistance to mercaptopurine Disp Tabs SE X BM (leucopenia/thrombocytopenia), NA /D, anorexia, stomatitis, rash, hyperuricemia, rare hepatotox Interactions t Bleeding W/ anticoagulants, NSAIDs, salicylates, thrombolytics EMS t Effects of anticoagulants/salicylates/ NSAIDs T risk of Infxn OD May cause NA, hypotension, and diaphoresis symptomatic and supportive... 

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. 

Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995 39 456 59. 

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. 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

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. 

It may perhaps be useful to remember that the dipole moments of the tautomers cannot and should not be considered as indicative of the relative values of such interactions in the first place, because appropriate calculations must be carried out in this case (as we have seen) in the monopole approximation and, second, because even in the dipole approximation, the mutual orientation of the dipoles of the interacting molecules is important. A glance at the data on the dipole moments of the different compounds mentioned here indicates that, in fact, there is no relation between the value of this moment in the different tautomers and the presence of such tautomers in the crystal. Thus, the dipole moments are predicted to be greater for the N(7)H form than for the N(9)H one in purine and adenine, but greater in the N(9)H form than in the N(7)H one in guanine, hypoxanthine, xanthine, 8-azaguanine, 8-azaxanthine, and 6-mercaptopurine. Also, no general relationship seems to exist between the relative values of the dipole moments and the stabilities of the different tautomers. 

UV-induced skin carcinogenesis by azthioprine (216), photochemical interaction between triamterene and hydrochlorthiazide (217) photochemistry of diclofenac (218), kinetic treatment of photochemical reactions (219) and a direct electron paramagnetic resonance (EPR) and spin-trapping study of light-induced free radicals from 6-mercaptopurine and its oxidation products (220). 

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. 

Clinically important, potentially hazardous interactions with altretamine, amikacin, aminoglycosides, antineoplastics, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, corticosteroids, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, estramustine, etoposide, fludarabine, fluorouracil, gemcitabine, gentamicin, hydroxyurea, idarubicin, ifosfamide, indomethacin, kanamycin, levamisole, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, neomycin, pentostatin, plicamycin, procarbazine, streptomycin, streptozocin, thioguanine, thiotepa, tobramycin, tretinoin, uracil, vinblastine, vincristine, vinorelbine... 

Clinically important, potentially hazardous interactions with acenocoumarol, amoxicillin, ampicillin, azathioprine, dicumarol, imidapril, mercaptopurine, pantoprazole, uracil/tegafur, vidarabine, zofenopril... 

Clinically important, potentially hazardous interactions with azathioprine or 6-mercaptopurine... 

Clinically important, potentially hazardous interactions with aminophylline, carbamazepine, cyclosporine, mercaptopurine, methotrexate, phenobarbital, prednisone, vincristine, warfarin... 

Clinically important, potentially hazardous interactions with antacids, azathioprine, basiliximab, cholestyramine, corticosteroids, cyclophosphamide, cyclosporine, daclizumab, hemophilus B vaccine, mercaptopurine, metronidazole, norfloxacin, tacrolimus, vaccines... 

Xanthine oxidase in the small intestine and liver converts mercaptopurine to thiouric acid, which is inactive as an immunosuppressive. Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine to more active metabolites such as 6-thioguanine and increases both immunosuppressive and potential toxic effects. Thus, patients on mercaptopurine should be warned about potentially serious interactions with medications used to treat gout or hyperuricemia, ami the dose should be decreased to 25% of the standard dose in subjects who are already taking allopurirwl. 

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. 

It may be prepared by the interaction of hypoxanthine with phosphorus pentasulphide. Mercaptopurine is found to inhibit experimental orthoimmune encephalomyletis and thyroiditis and hence used in combination with vincristine, methortrexate and prednisone in the treatment of childhood leukemia. As such 6-MP may cause hyperuricamia but it is usually administered with allopurinol—an analogue of hypoxanthine which blocks the conversion of 6-MP to uric acid and hence the dose of 6-MP is reduced and still the desired response is obtained. 

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. 

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