Drug reference

Mercaptopurine

Immunosuppressant · Treatment of Inflammatory Bowel Disease

ImmunosuppressantTreatment of Inflammatory Bowel Disease

CDSCO approvedSchedule H

EXCRETION

—

not curated

INTERACTIONS

12 major

incl. contraindicated

PREGNANCY

Avoid; teratogenic

FDA category + note

Top interactionssee all 12 →

FebuxostatContraindicatedDatabaseDDInter
AllopurinolSevereTextbook-citedKDT 7e · p948
AdalimumabSevereDatabaseDDInter
AllopurinolSevereDatabaseDDInter

Mechanism

Mercaptopurine (6-MP) is a purine antimetabolite that is converted intracellularly by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to thioinosinic acid, which inhibits multiple steps in purine biosynthesis including the conversion of inosine monophosphate to adenine and guanine nucleotides. The cytotoxic effect depends on incorporation of thioguanine nucleotides into DNA. Mercaptopurine is inactivated by thiopurine methyltransferase (TPMT) and xanthine oxidase; patients with TPMT deficiency require 85-90% dose reductions, and concurrent allopurinol (a xanthine oxidase inhibitor) mandates a 75% dose reduction.

Indications

Crohn's disease (unlicensed indication)Induction of remission in Crohn's disease (off-label) (as add-on treatment with a corticosteroid or budesonide)Maintenance of remission in Crohn's disease (off-label) (as monotherapy, when previously used with a corticosteroid to induce remission)Maintenance of remission in Crohn's disease (off-label) (in patients not previously received these drugs, particularly those with adverse prognostic factors such as early age of onset, perianal disease, corticosteroid use at presentation, and severe presentations)severe IBDsteroid-resistant or steroid-dependent IBDadjunct to glucocorticoids and biologics in moderate-to-severe Crohn’s disease and ulcerative colitismaintenance of remission in both diseasesprevention or delay of recurrence of Crohn’s disease after surgical resectiontreatment of fistulas in Crohn’s diseasehuman leukemiasMaintenance therapy of acute lymphocytic leukemia (ALL)Crohn's diseaseUlcerative colitisChildhood acute leukaemiaChoriocarcinomaSome solid tumours

Dosing

Adult: ALL maintenance: 2.5 mg/kg daily or 50-75 mg/m² daily, adjusted per response. IBD (Crohn's/UC): 1-1.5 mg/kg daily. CRITICAL: reduce to ONE-QUARTER dose with concurrent allopurinol. Screen TPMT/NUDT15 before starting.
Pediatric: Dosed per kg or m²; same TPMT considerations
Renal adjustment: Reduce dose in renal impairment
Hepatic adjustment: Reduce dose; monitor hepatic function closely
Max dose: Titrate to response; no fixed max — guided by WBC/neutrophil count

Pharmacokinetics

Half-life

Plasma t1/2 is limited by its relatively rapid (i.e., within 1–2 h) uptake into erythrocytes and other tissues.

Bioavailability

10%–50% (oral)

Protein binding

Testing for TPMT polymorphisms prior to treatment is recommended as low levels of erythrocyte TPMT activity are associated with increased drug toxicity.

Metabolism

Subject to first-pass metabolism by xanthine oxidase in the liver. Rapid metabolic degradation by xanthine oxidase and thiopurine methyltransferase (TPMT). HGPRT-catalyzed anabolism, methylation of sulfhydryl group and subsequent oxidation, oxidation by xanthine oxidase to 6-thiourate (inactive metabolite).

Excretion

Large percentage of administered sulfur appears in the urine as inorganic sulfate.

Contraindications

Absent TPMT activity (unless specialist supervision)

Side effects

Common

Bone marrow depressionNauseaAnorexiaHepatotoxicityLeucopeniaThrombocytopeniafeverrasharthralgiasvomitingMyelosuppression (thrombocytopenia, granulocytopenia, anemia, delayed onset)JaundiceHepatic enzyme elevationsSquamous cell malignancies of the skinReversible jaundiceHyperuricaemia

Serious

Fatal hepatotoxicity
Severe myelosuppression (TPMT-deficient patients)
Pancreatitis
Secondary malignancy
pancreatitis (about 5% of patients)
bone marrow suppression (major dose-related effect)
elevations in liver function tests (dose-related)
cholestatic hepatitis (relatively rare)
increased incidence of malignancy (non-Hodgkin lymphoma, 4-fold increase)
Bone marrow aplasia (in patients with TPMT polymorphic alleles)
Life-threatening toxicity (in patients with TPMT polymorphic alleles)
Opportunistic infection (e.g., reactivation of hepatitis B, fungal infection, Pneumocystis pneumonia)
Acute myeloid leukemia (AML) (after prolonged therapy for Crohn’s disease)
Bone marrow depression
Myelosuppression
Mucositis
Gut damage

Pregnancy & lactation

Pregnancy

Avoid; teratogenic

Drug interactions

Febuxostat

Contraindicated

Database

Increased plasma levels of mercaptopurine.

Concomitant use is contraindicated. If mercaptopurine is essential, an alternative to febuxostat should be considered, or mercaptopurine dose must be drastically reduced (e.g., to 1/10th of the usual dose) with very close monitoring of blood counts, which is generally not recommended due to high risk.

Source: DDInter

Allopurinol

Severe

Textbook-cited

Accumulation and toxicity of 6-MP/azathioprine (myelosuppression)

Reduce 6-MP or azathioprine dose to one-third when co-administered

Source: KDT 7e · p948

Adalimumab

Severe

Database

Drug interaction classified as: synergy.

Source: DDInter