Pharmacokinetics azathioprine

Pharmacokinetics Azathioprine is well absorbed following oral administration. Blood levels are of little value for therapy because the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. 

Drug interactions In a randomized, double-blind study, Zenapax or placebo was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and steroids to assess tolerability, pharmacokinetics, and drug interactions. The addition of Zenapax did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The following medications have been administered in clinical trials with Zenapax with no incremental increase in adverse reactions cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. 

PURINE ANALOGS AZATHIOPRINE 6-MERCAPTOPURINE Pharmacokinetics Pharmacodynamics... 

Azathioprine [a zah THIO preen] has been the cornerstone of immunosuppressive therapy over the last several decades. It has a nitroimidazoloyl side chain attached to the sulfur of 6-mercap-topurine, which is removed by non-enzymatic reduction in the body by glutathione to yield 6-mercaptopurine (6-MP). The latter is then converted to the corresponding nucleotide, thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthine-gua-nine phosphoribosyl transferase. The immunosuppressant effects of azathioprine are due to this fraudulent nucleotide. (See pp. 380-381 for a discussion of 6-MP s mechanism of action, resistance, pharmacokinetics, and adverse effects.) Because of their rapid proliferation in the immune response, and their dependence on de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. The drug has little effect on suppressing a secondary immune response. 

A feature of the pharmacologic action of azathioprine is its delayed onset, which may take 8-12 weeks to become apparent, possibly due to the slow accumulation of 6-TGN within the cells. The same is not necessarily true for the toxic effects of azathioprine, some of which may occur at any time during treatment (e.g., bone marrow suppression). Azathioprine appears to be a more potent immunosuppressive agent than does 6-MP itself, which may reflect differences in the pharmacodynamics and pharmacokinetics of the two compounds, as well as the relative abundance of different metabolites which are formed after their administration. Studies with hepatocytes have found that azathioprine toxicity involves depletion of reduced glutathione leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was... 

Disposition and Pharmacokinetics Azathioprine is well absorbed orally and reaches maximum blood levels within 1-2 hours after administration. The tj of azathioprine is 10 minutes, while that of its metabohte 6-mercaptopurine is about an hour. Blood levels have limited predictive value because of extensive metabolism, significant activity of many different metabolites, and high tissue levels attained. Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. Both are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance has little impact on biological effectiveness or toxicity, but the dose should be reduced in patients with renal failure. 

Moravek J, MatouSovic K, Prdt V, Sedivy J. Pharmacokinetics of roxithromycin in kidney grafted patients under cyclosporin A or azathioprine immunosupfressicn and in healthy volunteers. IntJ Clin Pharmacol Ther Toxicol (1990) 28,262-7. 

A study in kidney transplant patients taking corticosteroids, azathioprine and ciclosporin found that the pharmacokinetics of the ciclosporin were not significantly changed by pefloxacin 400 mg twice daily for 4 days. ... 

A study found that the pharmacokinetics of methylprednisolone in patients taking cielosporin and azathioprine varied widely between individual kidney transplant patients, but the mean values were similar to those found in normal subjects. ... 

A pharmacokinetic study in 40 patients found that the clearance of prednisolone was reduced by about 30% in those taking ciclosporin when compared with those taking azathioprine. ... 

---