6-Thioguanine metabolism

Factors that affect drug metabolism will influence the development of serious adverse effects. TPMT, one of the three enzymes that metabolize 6-MP, is encoded by a gene on chromosome 6 that contains functional polymorphisms. Multiple variants have been described ( 2, 3A, 3B, 3C, 3D, 4, 5, 6, 7, 10 31,32) that result in lower TPMT activity, leading to preferential metabolism of 6-MP by the HGPRT enzyme. This results in an increase in the amount of cytotoxic thioguanine nucleotides and greater myelotoxicity. There appears to be an allele dose-dependent... 

Fig. 14.2 Scheme of thiopurine drug metabolism. HPRT, hypoxanthine phosphoribosyl transferase 6-MMP, 6-methylmercaptopurine 6-TGN, 6-thioguanine nucleotides 6-TIMP, 6-thiosine monophosphate TPMT, thiopurine methyltransferase XO, xanthine oxidase... 

It has been suggested that thioguanine s multistep inhibition, one step of which is the inhibition of phosphoribosylpyrophosphate amidotransferase, results in a profound lowering of the intracellular concentration of guanine nucleoside phosphates and that this depletion causes a marked depression in cellular metabolism that presumably would lead to cell death [91 ]. 

Another guanine analogue, thioguanine, is also incorporated into both DNA and RNA of mammalian cells [198], and a correlation between its antitumour activity and the extent of its incorporation into DNA has been observed [339,340], although some investigators feel that the metabolic effects of thioguanylic acid may be more universally important [13, 91, 341]. The incorporation of a- and... 

Absorption of orally administered 6-thioguanine is slow and incomplete only approximately 30% of the oral dose is achieved in the plasma, peak levels being reached after 8 hours. Thioguanine is extensively metabolized prior to excretion. The elimination half-life is on the order of 80 minutes. 

Dose-related myelosuppression is the major adverse effect produced by 6-thioguanine. Patients deficient in thiopurine methyltransferase (TPMT), a cytosolic enzyme required for metabolism of 6-thioguanine, are at heightened risk. Other adverse effects include gastrointestinal complaints and elevations of liver transaminases. There have been rare reports of more serious he-patotoxicity, including acute hepatitis, acute cholestasis, and hepatic venoocclusive disease. 

Treatment of Childhood Acute Lymphoblastic Leukemia Thiopurines in the Treatment of Childhood Acute Lymphoblastic Leukemia Metabolism of 6-Mercaptopurine and 6-Thioguanine... 

TGN represents the sum of 6-thioguanosine monophosphate (6-thio-GMP), -diphosphate (6-thio-GDP) and -triphosphate (6-thio-GTP). In contrast, both TPMT and XO are the predominant catabolic enzymes in the metabolism of thiopurines. TPMT catalyses the X-adenosyl-L-methionine dependent S-methylation of 6-MP and its metabolites into 6-methyl-mercaptopurine (6-MMP), 6-methyl-mercaptopurine ribonucleotides (6-MMPR) such as 6-methylthioinosine monophosphat (meTIMP), and 6-methyl-thioguanine nucleotides (6-MTGN) (93). 

Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol 1998 42 266-272. 

The metabolism of azathioprine is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug if dosage is not adjusted. 

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

Mercaptopurine and thioguanine are both given orally (Table 55-3) and excreted mainly in the urine. However, 6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation catalyzed by xanthine oxidase, whereas 6-TG requires deamination before it is metabolized by this enzyme. This factor is important because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used with chemotherapy in hematologic cancers to prevent hyperuricemia after tumor cell lysis. It does this by blocking purine oxidation, allowing excretion of cellular purines that are relatively more soluble than uric acid. Nephrotoxicity and acute gout produced by excessive uric acid are thereby prevented. Simultaneous therapy with allopurinol and 6-MP results in excessive toxicity unless the dose of mercaptopurine is reduced to 25% of the usual level. This effect does not occur with 6-TG, which can be used in full doses with allopurinol. 

The molecular basis for the therapeutic effects of the purine analogs is unknown. Intracellular 6-thioguanine causes inhibition of purine nucleotide metabolism and DNA synthesis and repair, resulting in inhibition of cell division and proliferation. 

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

The chemical structure of 6-thioguanine, which results from the metabolism of azathioprine/mercaptopurine, is very similar to that of mercaptopurine. Therefore, a history of previous adverse effects with mercaptopurine should be anticipated in patients considered for 6-thioguanine treatment. 

The 2 -dcoxyribuse triphosphate anabolitc of thioguanine is extensively incorporated into DNA in place of the natural substrate. Thioguanine is metabolized to methylthioguanine, thiouric acid, methylthioxanthine, and thioxanthine. 

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