Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Fontus Health Ltd, 60 Lichfield Street, Walsall WS4 2BX, United Kingdom
Pharmacotherapeutic group: Antineoplastic agents, Antimetabolites, Purine analogues
ATC-Code: L01BB02
6-mercaptopurine is sulphydryl analogue of the purine bases, adenine and hypoxanthine, and acts as a cytotoxic antimetabolite.
6-mercaptopurine is an inactive pro-drug that acts as purine antagonist after cellular uptake and intracellular conversion into thioguanine-nucleotides (TGN) for cytotoxicity.
6-mercaptopurine metabolites suppress the de novo synthesis of purine and purine-nucleotide formation. The thioguanine nucleotides are also incorporated into nucleic acids and this leads to the cytotoxic effect of the drug.
The cytotoxic effect of 6-mercaptopurine may be related to the levels of thioguanine nucleotides in red blood cells, but not to the plasma concentration of 6-mercaptopurine.
The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability'. When administered at a dosage of 75 mg/m² to seven paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%. The variable bioavailability probably results from the metabolism of a significant portion of 6-mercaptopurine during first-pass hepatic metabolism.
After oral administration of 6-mercaptopurine 75 mg/m² to 14 children with acute lymphoblastic leukaemia, the mean Cmax was 0.89μM, with a range of 0.29-1.82μM and Tmax was 2.2 hours with a range of 0.5-4 hours.
The mean relative bioavailability of 6-mercaptopurine was approximately 26% lower following administration with food and milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see Section 4.2 Posology and method of administration).
Concentrations of 6-mercaptopurine in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration (CSF: plasma ratios of 0.05 to 0.27). Concentrations in the CSF are higher after intrathecal administration.
6-mercaptopurine is extensively metabolized by many multi-step pathways to active and inactive metabolites. Because of the complex metabolism, inhibition of one enzyme does not explain all cases of lack of efficacy and/or pronounced myelosuppression. The predominant enzymes responsible for the metabolism of 6-mercaptopurine or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate dehydrogenase (IMPDH) and hypoxanthine guanine phosphribosyltransferase (HPRT). Additional enzymes involved in the formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase (ITPase). There are also multiple inactive metabolites formed via other pathways.
There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of 6-mercaptopurine may predict adverse drug reactions to 6-mercaptopurine therapy. For example, individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations (see Section 4.4).
In a study with 22 adult patients the mean 6-mercaptopurine clearance and half-life after IV infusion was 864 mL/min/m² and 0.9 hours respectively. The mean renal clearance reported in 16 of these patients was 191 mL/min/m². Only about 20% of the dose was excreted in the urine as intact medicinal product after IV administration. In a study with 7 children patients the mean 6-mercaptopurine clearance and half-life after IV infusion was 719 ( + / - 610) ml/min/m² and 0.9 ( + / - 0.3) hours respectively.
No specific studies have been carried out in the elderly (see Section 4.2 Posology and method of administration).
Studies with a pro-drug of 6-mercaptopurine have shown no difference in 6-mercaptourine pharmacokinetics in uremic patients compared to renal transplant patients. Little is known about the active metabolites of 6-mercaptopurine in renal impairment (see Section 4.2 Posology and method of administration).
6-mercaptopurine and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hours.
A study with a pro-drug of 6-mercaptopurine was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease (see Section 4.2 Posology and method of administration).
6-mercaptopurine is mutagenic in man and chromosome damage has been reported in mice, rats and man.
In view of its action on cellular deoxyribonucleic acid (DNA) 6-mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment.
6-mercaptopurine causes growth arrest, severe embryo-lethality and teratogenic effects in mice, rats, hamsters and rabbits (such as cleft palate, eye and skeletal malformations) at doses that are nontoxic to pregnant females. 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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