Pharmacotherapeutic group: Anti-neoplastic and immunomodulating agent/purine analogue. ATC code: L01BB03.
Pharmacology: Pharmacodynamics: Thioguanine is a sulphydryl analogue of guanine and behaves as a purine antimetabolite. It is activated to its nucleotide, thioguanylic acid.
Thioguanine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. Thioguanine is also incorporated into nucleic acids and DNA (deoxyribonucleic acid) incorporation is claimed to contribute to the agent's cytotoxicity.
There is usually a cross-resistance between thioguanine and mercaptopurine: it is therefore not to be expected that patients with a tumour resistant to one will respond to the other.
Pharmacokinetics: Absorption: Studies with radioactive thioguanine show that peak blood levels of total radioactivity are achieved about 8 to 10 h after oral administration and decline slowly thereafter. Later studies using HPLC have shown 6-thioguanine to be the major thiopurine present for at least the first 8 h after intravenous administration. Peak plasma concentrations of 61 to 118 nanomol (nmol)/ml are obtainable following intravenous administration of 1 to 1.2 g of 6-thioguanine/m2 body surface area. Plasma levels decay biexponentially with initial and terminal half lives of 3 and 5.9 h, respectively.
Following oral administration of 100 mg/m2, peak levels as measured by HPLC occur at 2 to 4 h and lie in the range of 0.03 to 0.94 micromolar (0.03 to 0.94 nmol/ml). Levels are reduced by concurrent food intake (as well as vomiting).
Distribution: Limited data on the distribution of TG in humans are available in the scientific literature.
6-TG penetrates into the CSF following constant IV infusion administration after doses of 20 mg/m2/h over 24 hours in children with ALL.
Biotransformation: Thioguanine is extensively metabolised in vivo. The four different enzymes responsible for 6-TG metabolism are as follows: hypoxanthine (guanine) phosphoribosyl transferase (H(G)PRT), which converts 6-TG into thioguanosine monophosphate (6-TGMP), which is further metabolized by protein kinases to the active species, thioguanine nucleotides (6-TGN); TPMT, which converts 6-TG to 6-methylthioguanine (6-MTG, inactive metabolite) as well as 6-TGMP to 6-methyl-TGMP (an inactive metabolite) and xanthine oxidase (XDH or XO) and aldehyde oxidase (AO), which also convert 6-TG into inactive metabolites. 6-TG is initially deaminated by guanine deaminase (GDA) to form 6-thioxanthine (6-TX) and this becomes a substrate for the XDH catalysed formation of 6-thiouric acid (6-TUA).
NUDT15 R139C (NUDT15 c.415C>T) Variant: Recent studies indicate that a strong association exists between the NUDT15 variant NUDT15 c.415C>T [pArg139Cys] (also known as NUDT15 R139C [rs116855232], which is thought to lead to a loss of function of the NUDT15 enzyme, and thiopurine-mediated toxicity such as leukopenia and alopecia. The frequency of NUDT15 c415C>T has an ethnic variability of 9.8% in East Asians, 3.9% in Hispanics, 0.2% in Europeans and 0.0% in Africans, indicating an increased risk for the Asian population. Patients who are NUDT15 variant homozygotes (NUDT15 T risk alleles) are at an excessive risk of thiopurine toxicity compared with the C homozygotes.
Reduced thiopurine doses of patients who carry the NUDT15 variants may decrease their risk of toxicity. Therefore, genotypic analysis determining NUDT15 genotype should be determined for all patients, including paediatric patients, prior to initiating thiopurine treatment (see Dosage & Administration). The prescribing physician is advised to establish whether dose reduction is required based on patient response to treatment as well as their genetic profile.
Patients with variants in both the NUDT15 and TPMP enzymes are significantly less tolerant of thiopurines than those with risk alleles in only one of these two genes.
The precise mechanism of NUDT15-associated thiopurine-related toxicity is not understood.