Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Douglas Pharmaceuticals Ltd, P O Box 45 027, Auckland 0651, New Zealand Phone: (09) 835 0660
Pharmacotherapeutic group: immunosuppressant
ATC code: L04AX01
Azathioprine is an imidazolyl derivative of 6-mercaptopurine (6-MP). It is rapidly broken down invivo into 6-MP and a methylnitroimidazole moiety. The 6-MP readily crosses the cell membrane and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The rate of conversion varies from one person to another.
Nucleotides do not traverse cell membranes and therefore do not circulate in body fluids. Irrespective of whether it is given directly or is derived from in vivo from azathioprine, 6-MP is eliminated mainly as the inactive oxidised metabolite thiouric acid.
This oxidation is brought about by xanthine oxidase, an enzyme which is inhibited by allopurinol. The activity of the methylnitroimidazole moiety has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.
Determinations of plasma concentrations of azathioprine or 6-MP have no prognostic value as regard effectiveness or toxicity of these compounds.
While the precise modes of action remain to be elucidated, some suggested mechanisms include:
1. the release of 6-MP which acts as a purine antimetabolite.
2. the possible blockade of -SH groups by alkylation.
3. the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.
4. damage to deoxyribonucleic acid (DNA) through incorporation of purine thio-analogues.
Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment.
Azathioprine appears to be well absorbed from the upper gastrointestinal tract.
Studies in mice with 35S-azathioprine showed no unusually large concentration in any particular tissue, but there was very little 35S found in the brain.
Plasma levels of azathioprine and 6-mercaptopurine do not correlate well with the therapeutic efficacy or toxicity of azathioprine.
Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 mg/kg body weight/day over the period of organogenesis have shown varying degrees of foetal abnormalities.
Teratogenicity was evident in rabbits at 10 mg/kg bodyweight/day.
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