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Pharmacology: Pharmacodynamics: Mechanism of Action: Azathioprine is an imidazole derivate of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and a methylnitroimidazole moiety. The 6-MP readily croses cell membranes and is converted intracellulary 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 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 that is inhibited by allopurinol. Other potential mechanisms of azathioprine include the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response. Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment.
The activity of the methylnitroimidazole moiety, a metabolite of azathioprine but not 6-MP, has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.
Pharmacodynamic Effects: Plasma levels of azathioprine and 6-MP do not correlate well with the therapeutic efficacy or toxicity of azathioprine, and therefore have no prognostic value.
Pharmacokinetics: Absorption: The absorption of azathioprine is incomplete and variable. The median (range) absolute bioavailability of 6-MP after administration of azathioprine 50 mg is 47% (27-80%). The extent of absorption of azathioprine is similar across the gastrointestinal tract, including the stomach, jejunum, and cecum. However, the extent of 6-MP absorption, after azathioprine administration is variable and differs between the sites of absorption, with the highest extent of absorption in the jejunum, followed by the stomach and then the cecum.
Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-MP have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-MP was approximately 26% lower following administration with food and milk compared to an overnight fast. 6-MP is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes). Azathioprine should be administered at least one hour before or three hours after food or milk.
Distribution: The volume of distribution at steady state (Vdss) of azathioprine is unknown. The mean (±SD) apparent Vdss of 6-MP is 0.9 (±0.8) L/kg, although this may be an underestimate because 6-MP is cleared throughout the body (and not just in the liver).
It is predicted that 30% of azathioprine is protein bound.
Concentrations of 6-MP in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration of 6-MP.
Special Patient Populations: Elderly: No specific studies have been carried out in the elderly.
Overweight paediatric population: In a US clinical study, 18 children (aged 3 to 14 years) were evenly divided into two groups; either a weight to height ratio above or below the 75th percentile. Each child was on maintenance treatment of 6-MP and the dosage was calculated based on their body surface area. The mean AUC (0-∞) of 6-MP in the group above the 75th percentile was 2.4 times lower than that for the group below the 75th percentile. Therefore, children considered to be overweight may require azathioprine doses at the higher end of the dose range and close monitoring of response to treatment is recommended.
Renal Impairment: It has been suggested that the toxicity of azathioprine may be enhanced in the presence of renal insufficiency, but controlled studies have not supported this suggestion. Nevertheless, it is recommended that the dosage used should be at the lower end of the normal range and the haematological response should be carefully monitored. Dosage should be further reduced if haematological toxicity occurs.
Azathioprine and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of eight hours.
Hepatic Impairment: A study with azathioprine was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and six times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease. Therefore, consideration should be given to reducing the dosage in patients with impaired hepatic function (see Dosage & Administration).
Toxicology: Pre-clinical Safety Data: Mutagenicity: Azathioprine was found to be mutagenic in a number of in vitro and in vivo genotoxicity assays.
Carcinogenicity: Long-term carcinogenicity studies of azathioprine showed an increased incidence of lymphosarcomas, as well as epithelial tumours and carcinomas in mice and rats, respectively, at dosages of up to 2-fold the human therapeutic dose and at lower dosages in immunocompromised mice.
Reproductive Toxicology: Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5 to 15 mg/kg bodyweight/day over the period of organogenesis have shown varying degrees of foetal abnormalities.
Teratogenicity was evident in rabbits at 10 mg/kg body weight/day.
