Tioguanine

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Tioguanine
Tioguanine.svg
Systematic (IUPAC) name
2-amino-1H-purine-6(7H)-thione
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a682099
Legal status
?
Routes oral
Pharmacokinetic data
Bioavailability 30% (range 14% to 46%)
Metabolism Intracellular
Half-life 80 minutes (range 25-240 minutes)
Identifiers
CAS number 154-42-7 YesY
ATC code L01BB03
PubChem CID 2723601
DrugBank DB00352
ChemSpider 2005804 YesY
UNII WIX31ZPX66 YesY
KEGG D08603 YesY
ChEBI CHEBI:9555 N
ChEMBL CHEMBL727 YesY
Chemical data
Formula C5H5N5S 
Mol. mass 167.193 g/mol
 N (what is this?)  (verify)

Tioguanine (INN, BAN), or thioguanine (AAN, USAN), also commonly referred to as 6-thioguanine (6-TG); the trade name is Lanvis (Manufacturer: GlaxoSmithKline), formerly under the trade name Tabloid. 6-TG belongs to the thiopurine family of drugs that also include mercaptopurine and azathioprine, which are examples of antimetabolites. It is a purine analogue of the nucleobase guanine.

Its drug usage was originally as a cytostatic agent in chemotherapy for the treatment of acute lymphoblasic leukemia in children,[1] but has been used less frequently in recent years because of safety concerns. However, it is becoming more widely used for treating ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), and some autoimmune diseases. It is a pale yellow, odorless, crystalline powder.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Medical uses[edit]

Adults[edit]

Children and adolescents[edit]

Side effects[edit]

Hepatic veno-occlusive disease and nodular regenerative hyperplasia[edit]

The major concern that has inhibited the use of thioguanine has been VOD and its histological precursor NRH. The incidence of NRH with thioguanine was reported as between 33-76%.[4] The risk of ensuing VOD is serious and frequently irreversible so this side effect has been a major concern. However, recent evidence using an animal model for thioguanine-induced NRH/VOD has shown that, contrary to previous assumptions, NRH/VOD is dose dependent and the mechanism for this has been demonstrated.[5] This has been confirmed in human trials, where thioguanine has proven to be safe but efficacious for coeliac disease when used at doses below those commonly prescribed.[1] This has led to a revival of interest in thioguanine because of its higher efficacy and faster action compared to other thiopurines and immunosuppressants such as mycophenylate.[6]

Contraindications[edit]

  • Pregnancy
  • Lactation: The safety warning against breastfeeding may have been a conservative assessment, but research evidence suggests that thiopurines do not enter breastmilk.[7]

Interactions[edit]

Cancers that do not respond to treatment with mercaptopurine do not respond to thioguanine. On the other hand, some cases of IBD that are resistant to mercaptopurine (or its pro-drug azathioprine) may be responsive to thioguanine.

Metabolism and pharmacokinetics[edit]

A single oral dose of thioguanine has incomplete metabolism, absorption and high interindividual variability. The bioavailability of thioguanine has an average of 30% (range 14-46%). The maximum concentration in plasma after a single oral dose is attained after 8 hours.

Thioguanine, like other thiopurines, is cytotoxic to white cells; as a result it is immunosuppressive at lower doses and anti-leukemic/anti-neoplastic at higher doses. Thioguanine is incorporated into human bone marrow cells, but like other thiopurines, it is not known to cross the blood-brain barrier. Thioguanine cannot be demonstrated in cerebrospinal fluid, similar to the closely related compound 6-mercaptopurine which also cannot penetrate to the brain.

The plasma half-life of thioguanine is short, due to the rapid uptake into liver and blood cells and conversion to 6-TGN. The median plasma half-life of 80-minutes with a range of 25–240 minutes. Thioguanine is excreted primarily through the kidneys in urine, but mainly as a metabolite, 2-amino-6-methylthiopurine. However, the intra-cellular thio-nucleotide metabolites of thioguanine (6-TGN) have longer half-lives and can therefore be measured after thioguanine is eliminated from the plasma.

Thioguanine is catabolized (broken down) via two pathways.[8] One route is through the deamination by the enzyme guanine deaminase to 6-thioxanthine, which has minimal anti-neoplastic activity, then by oxidation by xanthine oxidase of the thioxanthine to thiouric acid. This metabolic pathway is not dependent on the efficacy of xanthine oxidase, so that the inhibitor of xanthine oxidase, the drug allopurinol, does not block the breakdown of thioguanine, in contrast to its inhibition of the breakdown of the related thiopurine 6-mercaptopurine. The second pathway is the methylation of thioguanine to 2-amino-6-methylthiopurine, which is minimally effective as an anti-neoplastic and significantly less toxic than thioguanine. This pathway also is independent of the enzyme activity of xanthine oxidase.

Mechanism of action[edit]

6-Thioguanine is a thio analogue of the naturally occurring purine base guanine. 6-thioguanine utilises the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) to be converted to 6-thioguanine monophosphate (TGMP). High concentrations of TGMP may accumulate intracellularly and hamper the synthesis of guanine nucleotides via the enzyme Inosine monophosphate dehydrogenase (IMP dehydrogenase).[9]

TGMP is converted by phosphorylation to thioguanine diphosphate (TGDP) and thioguanine triphosphate (TGTP). Simultaneously deoxyribosyl analogs are formed, via the enzyme ribonucleotide reductase. The TGMP, TGDP and TGTP are collectively named 6-thioguanine nucleotides (6-TGN). 6-TGN are cytotoxic to cells by: (1) incorporation into DNA during the synthesis phase (S-phase) of the cell; and (2) through inhibition of the GTP-binding protein (G protein) Rac1, which regulates the Rac/Vav pathway.[10] An additional effect may be derived from the incorporation of 6-thioguanine into RNA. This yields a modified RNA strand which cannot be read by the ribosomes.

Administration[edit]

Thioguanine is administered orally (as a tablet - 'Lanvis').

Synthesis[edit]

References[edit]

  1. ^ a b Vora A, Mitchell CD, Lennard L, et al. (October 2006). "Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial". Lancet 368 (9544): 1339–48. doi:10.1016/S0140-6736(06)69558-5. PMID 17046466. 
  2. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ Mason C, Krueger GG (January 2001). "Thioguanine for refractory psoriasis: a 4-year experience". J. Am. Acad. Dermatol. 44 (1): 67–72. doi:10.1067/mjd.2001.109296. PMID 11148479. 
  4. ^ Dubinsky MC, Vasiliauskas EA, Singh H, et al. (2003). "6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.". Gastroenterology 125 (2): 298–303. doi:10.1016/S0016-5085(03)00938-7. PMID 12891528. 
  5. ^ Oancea I, Png CW, Das I, Lourie R, Winkler IG, et al. (July 2012). "A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity.". Gut. Epub ahead of print (4): 594–605. doi:10.1136/gutjnl-2012-302274. PMID 22773547. 
  6. ^ Van Asseldonk DP, Oancea I, Jharap B, et al. (March 2012). "Is thioguanine-associated sinusoidal obstruction syndrome avoidable? Lessons learned from 6-thioguanine treatment of inflammatory bowel disease and a mouse model.". Rev Assoc Med Bras 58 (Suppl.1): S8–13. 
  7. ^ Gardiner SJ, Gearry RB, Roberts RL, et al. (2006). "Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs.". Br J Clin Pharmacol. 62 (4): 453–6. doi:10.1111/j.1365-2125.2006.02639.x. PMC 1885151. PMID 16995866. 
  8. ^ Oncea I, Duley J. (2008). "Pharmacogenetics of Thiopurines.". Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, published McGraw-Hill's Access Medicine (on-line) (11th ed.). Chapter 38. 
  9. ^ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy.". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163. 
  10. ^ de Boer NK, van Bodegraven AA, Jharap B, et al. (Dec 2007). "Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD.". Nat Clin Pract Gastroenterol Hepatol. 4 (12): 686–94. doi:10.1038/ncpgasthep1000. PMID 18043678. 

Website references[edit]

"Revista da Associação Médica Brasileira" (Journal of the Brazilian Medical Association), vol. 58,supplement 1, 2012; 3rd International Thiopurine Symposium. Free PDF available: http://www.ramb.org.br/edicao_atual/suplemento1.pdf

Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, published McGraw-Hill's Access Medicine (on-line), see: http://www.accessmedicine.com/updatesContent.aspx?aid=1001255