Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamics Properties

Pharmacotherapeutic group: anti-neoplastic and immunomudulating agent/purine analogue, ATC code: L01BB03.

Mechanism of action

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.

Pharmacodynamic Effects

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.

Pharmacokinetic Properties

5.2 Pharmacokinetics Properties

Absorption
Studies with radioactive thioguanine show that peak blood levels of total radioactivity are achieved about 8-10 hours 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 hours after intravenous administration. Peak plasma concentrations of 61-118 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 hours, respectively. Following oral administration of 100 mg/m2, peak levels as measured by HPLC occur at 2-4 hours and lie in the range of 0.03-0.94 micromolar (0.03-0.94 nmol/ml). Levels are reduced by concurrent food intake (as well as vomiting).

Distribution

Limited data on the distribution of tioguanine in humans are available in the scientific literature.
Tioguanine penetrates into the CSF following constant IV infusion administration after doses of 20 mg/m2/h over 24 hours in children with ALL.

Biotransformation

Tioguanine is extensively metabolised in vivo.The four different enzymes responsible for tioguanine metabolism are as follows: hypoxanthine (guanine) phosphoribosyl transferase (H(G)PRT), which converts tioguanine into thioguanosine monophosphate (6-TGMP), which is further metabolized by protein kinases to the active species, thioguanine nucleotides (6-TGN); TPMT, which converts tioguanine 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 tioguanine into inactive metabolites. Tioguanine 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).

Elimination

No data.