Immunosuppressants pharmacokinetics

Mechanism of Action An alkylating agent that inhibits DNAand RNA protein synthesis by cross-linking with DNA and RNA strands, preventing cell growth. Cell cycle-phase nonspedflc. Therapeutic Effect Potent immunosuppressant. Pharmacokinetics Well absorbed from the G1 tract. Protein binding low. Crosses the blood-brain barrier. Metabolized in the liver to active metabolites. Primarily excreted in urine. Removed by hemodialysis. Half-life 3-12 hr. 

Yang Z, Peng Y, Wang S (2005) Immunosuppressants pharmacokinetics, methods of monitoring and role of high performance liquid chromatography/mass spectrometry. Clin Appl Immunol Rev 5 405 130... 

Although most CF patients have shorter half-lives and larger volumes of distribution than non-CF patients, some patients exhibit decreased clearance. Possible causes include concomitant use of nephrotoxic medications, presence of diabetic nephropathy, history of transplantation (with immunosuppressant use and/or procedural hypoxic injury), and age-related decline in renal function in older adult patients. Additionally, CF patients are repeatedly exposed to multiple courses of IV aminoglycosides, which can result in decreased renal function. Evaluation of previous pharmacokinetic parameters and trends, along with incorporation of new health information, is key to providing appropriate dosage recommendations. 

In addition to the numerous pharmacokinetic interactions seen with the maintenance immunosuppressants, there also exists the possibility for pharmacodynamic interactions. An in-depth review of pharmacodynamic interactions with maintenance immunosuppressive agents goes beyond the scope of this chapter. 

Alemtuzumab is the antibody to the CD52 receptor present on B and T lymphocytes. The pharmacokinetics of alemtuzumab demonstrate a terminal half-life of 7 days. Alemtuzumab has shown clinical activity in the treatment of chronic lymphocytic leukemia. Severe and prolonged (6 months) immunosuppression may result, which necessitates prophylaxis with cotrimox-azole and antivirals to prevent opportunistic infections. 

Budde K, Glander P, Grohmann J, Bauer S, Hambach P, Hepburn H, Mai I, Sandau K, Fischer W, Neumayer HH. (2004) Pharmacokinetic and pharmacodynamic comparison of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) in maintenance renal transplant patients with tacrolimus as basic immunosuppression (P736). Transplantation 78 459 60. 

Pharmacology Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. The mechanism of action of tacrolimus in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. Pharmacokinetics ... 

Mechanism of Action An immunosuppressive whose exact mechanism is unknown. May act by modifying immune processes thought to be responsible for the pathogenesis of mulfiple sclerosis (MS). Therapeutic Effect Slows progression of MS. Pharmacokinetics Substantial fraction of glatiramer is hydrolyzed locally. Some fraction of injected material enters lymphatic circulation, reaching regional lymph nodes some may enter systemic circulation intact. 

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. 

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. 

There are few studies of pharmacodynamics that are analyzed by sex and even fewer that combine pharmacokinetics and pharmacodynamics. The most information to date has been provided on the cardiovascular effects of drugs, followed by pharmacodynamic studies of analgesics, immunosuppressants, and antidepressants. 

Mai I, Kruger H, Budde K, Johne A, BrockmoUer J, Neumayer HH, Roots I. Hazardous pharmacokinetic interaction of Saint John s wort (Hypericum perforatum) tvith the immunosuppressant cyclosporin. Int J Chn Pharmacol Ther 2000 38(10) 500-2. 

Everolimus is an immunosuppressive macrolide that also has synergistic actions with ciclosporin and interrupts the proliferative responses of vascular and bronchial smooth muscle cells. In a phase I trial, its safety profile and pharmacokinetics were assessed during a 4-week course of once-daUy sequential ascending doses (0.75, 2.5, or... 

Burdmann EA, Andoh TF, Prado EAB, Franceschini N, FujiharaC,ZatzR, Bennett WM. Renal, immunosuppressive and pharmacokinetic effects ofthe substitution of intralipid (LIP) for cremophor (CRE) as vehicle for parenteral cyclosporine (CSA) administration. J Am Soc Nephrol 1995 6 995. 

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... 

Mai, I., Kruger, H., Budde, K., Johne, A., Brockmoller, J., Neumeyer, H.H., Roots, I. (2000) Hazardous pharmacokinetic interaction of St. John s wort (Hypericum perforatum) with the immunosuppressant cyclosporin. Int. J. Clin. Pharmacol. Then 38, 500-502. 

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