Imuran Pharmacology, Pharmacokinetics, Studies, Metabolism - Azathioprine

Imuran Pharmacology, Pharmacokinetics, Studies, Metabolism - Azathioprine

CLINICAL PHARMACOLOGY

Metabolism

Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at one to two hours after oral "S-azathioprine and decays with a half-life of five hours. This is not an estimate of the half-life of azathioprine itself but is the decay rate of all" S-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 pg/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 cleaved in viva to mercaptopurine. 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 eight hours. Conversion to inactive 6-thiouric acid by xanthine oxidase is an important degradativapathway, and the inhibition of this pathway in patients receiving allopurinol is the basis for the azathi- oprine dosage reduction required in these patients (see DRUG INTERACTIONS). 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 p.o. renal function.

Homograph Survival

Summary information from transplant centers and registnes indicates relatively universal use of azathioprine with or without other immunosuppressive agents. Although 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 variable 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 graft 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 mitogenic 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 auto-immune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine.

The mechanisms whereby azathioprine affects auto-immune diseases 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 preceded the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose- related. Azathioprine is considered a slowacting drug and effects may persist after the drug has been discontinued.