DRUG STUDY AND INFORMATION FORM Generic Name: 6-Mercaptopurine Trade Name: Purinethol Drug Class: Purine Analogs

(6-Thiopurine Analogs) Structure/Chemistry: Hypoxanthine analog with S substituted for O on carbon 6 for better transport into cells

Pharmacodynamics

Mechanism of Action: Excellent substrate for hypoxanthine guanine phosphoribosyl transferase (HGPRT), which converts mercaptopurine to 6-thioinosine-5-monophosphate (TIMP). T-IMP inhibits the new formation of ribosyl-5-phosphate, as well as conversion of inosine-5-monophosphate to adenine and guanine nucleotides.

Pharmacologic Effects: Inhibits purine synthesis and also becomes incorporated into nucleic acids, thereby preventing DNA and RNA synthesis.

Drug Resistance or Tolerance: Deficiency of the activating enzyme HGPRT or increased alkaline deficiency. Other possible mechanisms of resistance include decreased drug uptake, increased drug efflux, and alteration in allosteric inhibition of ribosylamine 5-phosphate synthase.

Pharmacokinetics

Absorption: For treatment of ALL, the oral dose is 50-100 mg/m2 and is thereafter adjusted according to white blood cell and platelet counts. Oral ingestion results in only 10-50% absorption due to first-pass metabolism by xanthine oxidase in the liver. Reduce dose by 75% when giving xanthine oxidase inhibitors such as allopurinol. Distribution: Efflux system prevents mercaptopurine from reaching the brain.

Elimination: t1/2 of 50 mins in plasma after IV dose; rapidly metabolized by xanthine oxidase and thiopurine methyltransferase (TPMT)

Metabolism: Rapidly metabolized by xanthine oxidase and thiopurine methyltransferase (TPMT). Xanthine oxidase oxidizes mercaptopurine to 6-thiouric acid, an inactive metabolite. TPMT is an enzyme with many polymorphic alleles that methylates the sulfur group on mercaptopurine.

Adverse Side Effects/Toxicity: Primarily bone marrow depression (delayed with folic acid antagonists) but also anorexia, nausea, vomiting. Possibly also jaundice and hepatic enzyme elevations in one-third of patients. Predisposes to opportunistic infections and is teratogenic during first trimester. Low activity of TPMT is associated with increased toxicity. Those with autoimmune disease and low TPMT may experience bone marrow aplasia and life-threatening toxicity. Drug Interactions: Food and oral antibiotics decrease absorption. Absorption increased when combined with high-dose methotrexate. Methotrexate is synergistic by inhibiting the earliest steps of purine synthesis and by increasing the cofactor PRPP (5-phosphoribosyl-1-pyrophosphate) for mercaptopurines activation. Therapeutic uses: ALL (acute lymphoblastic leukemia)

Miscellaneous: