In this article, we will discuss Azathioprine (Mechanism of Action). So, let’s get started.
Mechanism of Action
Homograft Survival: The use of azathioprine for inhibition of renal homograft rejection is well established the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes vanable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graf rejections or secondary responses.
Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogen responses, serum immunoglobulins, and secondary antibody responses are usually normal.
Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example the severity of adjuvant anthritis is reduced by azathioprine.
The mechanisms whereby azathioprine affects autoimmune discases are not known. Azathioprine is immunosuppressive, delayed
hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow acting drug and effects may persist after the drug has been discontinued.
Clinical Pharmacology
Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral ³⁵S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all ³⁵S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL.). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable.
Azathioprine is metabolized to 6-mercaptopurinc (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver, no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites. The cytotoxicity of azathioprine is due, in part, to
the incorporation of 6-TGN into DNA.
6-MP undergoes two major inactivation routes. One is thiol methylation, which is catalyzed by the enzyme thiopurines
methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The nucleotide diphosphatase (NUDT15) enzyme is involved in conversion of the 6-TGNs to inactive 6-TG monophosphates. TPMT activity correlates inversely with 6-TGN levels in crythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation
pathway) activities.
Genetic polymorphisms influence TPMT and NUDT15 activity. Several published studies indicate that patients with reduced TPMT or NUDT15 activity receiving usual doses of 6-MP orazathioprine, accumulate excessive cellular concentrations of active 6-TGN, and are at higher risk for severe myelosuppression. Because of the risk of toxicity, patients with TPMT or NUDT15 deficiency require alternative therapy or dose modification.
Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function alleles of the TPMT gene and have little or no TPMT activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function TPMT allele leading to intermediate TPMT activity (heterozygous deficient or intermediate metabolizers). The TPMT*2, TPMT*3A, and TPMT*3C alleles account for about 95% of individuals with reduced levels of TPMT activity. NUDT15 deficiency is detected in <1% of patients of European or African ancestry. Among patients of East Asian ancestry (i.e. Chinese, Japanese, Vietnamese). 2%
have two loss-of-function alleles of the NUDT15 gene, and approximately 21% have one loss-of-function allele. The p.R139C variant of NUDT15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function NUDT15 alleles have been observed.
Inhibition of xanthine oxidase (XO) may cause increased plasma concentrations of azathioprine or its metabolites leading to toxicity. Proportions of metabolites are different in individual patients and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function.