Tioguanine

(BAN, rINN)
Tioguanine Chemical formula
Synonyms: NSC-752; 6-TG; Thioguanine Tioguanin; Tioguanina; Tioguaninum; WR-1141. 2-Aminopurine6(1H)-thione; 2-Amino-6-mercaptopurine; 2-Aminopurine-6thiol.
Cyrillic synonym: Тиогуанин.

💊 Chemical information

Chemical formula: C5H5N5S = 167.2.
CAS — 154-42-7 (anhydrous tioguanine); 5580-03-0 (tioguanine hemihydrate).
ATC — L01BB03.
ATC Vet — QL01BB03.

Pharmacopoeias.

In Br., Chin., and US.

BP 2008

(Tioguanine). A pale yellow, crystalline powder. Practically insoluble in water, in alcohol, and in chloroform; dissolves in dilute solutions of alkali hydroxides.

USP 31

(Thioguanine). It is anhydrous or contains one-half molecule of water of hydration. A pale yellow, odourless or practically odourless, crystalline powder. Insoluble in water and in chloroform; soluble 1 in 7700 of alcohol; freely soluble in dilute solutions of alkali hydroxides. Store in airtight containers.

💊 Adverse Effects, Treatment, and Precautions

As for Mercaptopurine. In some patients, gastrointestinal reactions are reported to be less frequent than with mercaptopurine.

Effects on the blood.

For the view that it may be possible to predict those individuals likely to have severe bone-marrow depression with tioguanine based on measurement of the activity of thiopurine methyltransferase or the concentration of tioguanine nucleotide, see under Azathioprine.

Effects on the liver.

The use of tioguanine has been limited by reports of hepatic veno-occlusive disease attributed to the drug.1-4 The manufacturer (GlaxoSmithKline) has stated that, in most cases, liver toxicity is reversible upon withdrawal of chemotherapy. A comparison with mercaptopurine in the maintenance treatment of children with acute lymphoblastic leukaemia found that of 95 patients who developed veno-occlusive disease, 82 were receiving tioguanine, representing about 11% of all patients assigned to the drug.5 In addition, although tioguanine was associated with fewer CNS relapses, patients in the tioguanine arm were more likely to develop fatal infections. Centrilobular hepatic necrosis has also been reported; reports are confounded by the use of high doses of tioguanine, other antineoplastics, oral contraceptives, and chronic alcohol abuse.
1. Gill RA, et al. Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med 1982; 96: 58–60
2. Krivoy N, et al. Reversible hepatic veno-occlusive disease and 6-thioguanine. Ann Intern Med 1982; 96: 788
3. Kao NL, Rosenblate HJ. 6-Thioguanine therapy for psoriasis causing toxic hepatic venoocclusive disease. J Am Acad Dermatol 1993; 28: 1017–18
4. Romagosa R, et al. Treatment of psoriasis with 6-thioguanine and hepatic venoocclusive disease. J Am Acad Dermatol 2002; 47: 970–2
5. Vora A, et al. Medical Research Council/National Cancer Research Network Childhood Leukaemia Working Party. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 2006; 368: 1339–48.

Handling and disposal.

For reference to a method for the destruction of tioguanine in wastes, see Mercaptopurine.

💊 Interactions

Unlike mercaptopurine, normal doses of tioguanine may be used with allopurinol. A number of cases of portal hypertension with hepatic nodular regenerative hyperplasia have been reported in patients who received tioguanine with busulfan. It has been suggested that daunorubicin might enhance the hepatotoxicity of tioguanine.

💊 Pharmacokinetics

Tioguanine is incompletely and variably absorbed from the gastrointestinal tract; on average about 30% of a dose is absorbed after oral doses. It is rapidly activated in the body by intracellular conversion to its nucleotide, thioguanylic acid and its thioguanosine phosphate derivatives. With repeated doses increasing amounts of the nucleotide are incorporated into DNA. Very little unchanged tioguanine has been detected circulating in the blood but the half-life of the nucleotide in the tissues is prolonged. Tioguanine is inactivated primarily by methylation to aminomethylthiopurine; small amounts are deaminated to thioxanthine, and may go on to be oxidised by xanthine oxidase to thiouric acid, but inactivation is essentially independent of xanthine oxidase and is not affected by inhibition of the enzyme. It is excreted in the urine almost entirely as metabolites; only negligible amounts of tioguanine have been detected. Tioguanine does not appear to cross the blood-brain barrier to a significant extent; very little is found in CSF after normal clinical doses. It crosses the placenta.

💊 Uses and Administration

Tioguanine is an analogue of the naturally occurring purine, guanine, and is an antineoplastic with actions and uses similar to those of mercaptopurine. It appears to cause fewer gastrointestinal reactions but cross-resistance exists so that patients who do not respond to one are unlikely to respond to the other. Tioguanine may be given orally, usually with other antineoplastics, in the induction of remissions in acute myeloid leukaemia. It has also been used in other malignancies including acute lymphoblastic leukaemia and chronic myeloid leukaemia. Doses of between 100 and 200 mg/m 2 daily have been given at various stages of treatment for short term cycles; similar doses have been used in children. A dose of 2 mg/kg daily increased after 4 weeks, if there is no response or toxicity allows, to 3 mg/kg daily may be given to adults and children in those rare cases when single agent therapy is considered appropriate. Blood counts should be made frequently, particularly during induction and when tioguanine is given with other antineoplastics. Therapy should be withdrawn at the first sign of severe bone-marrow depression. Tioguanine is not recommended for long-term continuous therapy because of the high risk of hepatotoxicity (see Effects on the Liver, above). Tioguanine has been given intravenously as the sodium salt.

Psoriasis.

A report of the use of tioguanine, in doses ranging from 20 mg twice weekly to 120 mg daily, in the management of patients with refractory psoriasis.1 Dramatic improvement occurred in 14 of 18 patients, but a further 2 were unable to tolerate the drug. Myelosuppression was the principal toxic effect and it was suggested that thiopurine methyltransferase activity could be measured as a basis to determine initial dosage and the risk of toxicity. For the conventional management of psoriasis.
1. Mason C, Krueger GG. Thioguanine for refractory psoriasis. J Am Acad Dermatol 2001; 44: 67–72.

💊 Preparations

BP 2008: Tioguanine Tablets; USP 31: Thioguanine Tablets.

Proprietary Preparations

Arg.: Lanvis; Austral.: Lanvis; Belg.: Lanvis; Braz.: Lanvis; Canad.: Lanvis; Chile: Lanvis; Cz.: Lanvis; Fr.: Lanvis; Gr.: Lanvis; Hong Kong: Lanvis; Irl.: Lanvis; Israel: Lanvis; Malaysia: Lanvis; Neth.: Lanvis; NZ: Lanvis; Pol.: Lanvis; S.Afr.: Lanvis; Singapore: Lanvis†; Swed.: Lanvis; Switz.: Lanvis; Thai.: Lanvis; UK: Lanvis; USA: Tab l o id.
Published March 13, 2019.