Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Nova Laboratories Ireland Limited, 3<sup>rd</sup> Floor, Ulysses House, Foley Street, Dublin 1, D01 W2T2, Ireland
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, purine analogues
ATC code: L01BB02
6-mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to thioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The thioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the active substance.
Cross-resistance usually exists between 6-mercaptopurine and 6-thioguanine.
The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability, which probably results from its first-pass metabolism. When administered orally at a dosage of 75 mg/m² to 7 paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%.
In a comparative bioavailability study in healthy adult volunteers (n=60), 50mg of Xaluprine oral suspension was demonstrated to be bioequivalent to the reference 50mg tablet for AUC, but not Cmax. The mean (90% CI) Cmax with the oral suspension was 39% (22%-58%) higher than the tablet although there was less between-subject variability (% C.V) with the oral suspension (46%) than the tablet (69%).
The intracellular anabolism of 6-merpactopurine is catalysed by several enzymes to eventually form 6-thioguanine nucleotides (TGNs), but a variety of intermediary TGNs are formed en route to the TGNs. The first step is catalysed by hypoxanthine-guanine phosphoribosyl transferase yielding thioinosine monophosphate (TIMP). 6-mercaptopurine is also subject to S-methylation by the enzyme thiopurine S-methyltransferase (TPMT), yielding methylmercaptopurine, which is inactive. However,
TPMT also catalyses the S-methylation of the principle nucleotide metabolite, TIMP, to form methylthioinosine monophosphate (mTIMP). Both TIMP and mTIMP are inhibitors of phosphoribosyl pyrophosphate amidotransferase, an enzyme which is important in de novo purine synthesis. Xanthine oxidase is the main catabolic enzyme and it converts the 6-mercaptopurine into the inactive metabolite, 6-thiouric acid. This is excreted in the urine. Approximately 7% of an oral dose is excreted as unchanged 6-mercaptopurine within 12 hours after administration.
The elimination half-life of 6-mercaptopurine is 90 ± 30 minutes, but the active metabolites have a longer half-life (approximately 5 hours) than the parent compound. The apparent body clearance is 4832 ± 2562 ml/min/m². There is low entry of 6-mercaptopurine into the cerebrospinal fluid.
The main route of elimination for 6-mercaptopurine is by metabolism.
6-mercaptopurine, in common with other antimetabolites, is mutagenic and causes chromosomal aberrations in vitro and in vivo in mice and rats.
Given its genotoxic potential, 6-mercaptopurine is potentially carcinogenic.
6-mercaptopurine causes embryolethality and severe teratogenic effects in the mouse, rat, hamster and rabbit at doses that are non-toxic to the mother. In all species, the degree of embryotoxicity and the type of malformations are dependent on the dose and stage of the gestation at the time of administration.
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