Cyclosporine in blood

Ducharme MP, Provenzano R, Dehoorne-Smith M, Edwards DJ. Trough concentrations of cyclosporine in blood following administration with grapefruit juice. Br J Clin Pharmacol 1993 36(5) 457-459. 

H. L. Verrill, R. E. Girgis, R. E. Easterling, B. S. Malhi, and W. F. Mueller, Distribution of cyclosporine in blood of a renal transplant recipient with type V hyperlipoproteinemia, Clin. Chem. 33 423-428 (1987). 

C. Vidal, G.l. Kirchner, G. Wilnsch, K.-F. Sewing, Automated simultaneous quantification of the immunosuppressants 40-O-(2-hydroxyethyl) rapamycin and cyclosporin in blood with ESI-MSc detection, Clin. Chem., 44 (1998) 1275. 

Bowers, L.D. Cyclosporine analysis by high-performance liquid chromatography precision, accuracy, and minimum detectable quantity. Transplant.Proc., 1990, 22, 1150-1154 Gupta, S.K. Benet, L.Z. HPLC measurement of cyclosporine in blood plasma and urine and simultaneous measurement of its four metabolites in blood. J.Liq.Chromatogr., 1989, 12, 1451-1462 [cyclosporine A plasma urine simultaneous metabolites LOD 30 ng/mL cyclosporine D (IS) column temp 70]... 

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

Although tacrolimus therapy is associated with increasing blood pressure, studies have found that tacrolimus has less dramatic effects on GFR and RBF than cyclosporine. In some clinical trials, tacrolimus caused less severe HTN and required significantly fewer antihypertensive medications at both 24 and 60 months after transplantation than cyclosporine.61-63 Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to minimize blood pressure increases in transplant recipients. Conversion to sirolimus also may be an alternative to the calcineurin inhibitors in patients with difficult-to-treat HTN because sirolimus therapy is less associated with increased blood pressure. Additionally, withdrawal or tapering of steroid therapy may be an effective strategy for lowering blood pressure. 

Cyclosporine is not recommended for Crohn s disease except for patients with symptomatic and severe perianal or cutaneous fistulas. The dose of cyclosporine is important in determining efficacy. An oral dose of 5 mg/kg/ day was not effective, whereas 7.9 mg/kg/day was effective. However, toxic effects limit application of the higher dosage. Dosage should be guided by cyclosporine whole-blood concentrations. 

Salm et al.44 developed a high-throughput analytical method to measure cyclosporine in whole blood. They used a simple SPE procedure, followed by HPLC-MS/MS. An Agilent 1100 liquid chromatograph was coupled with an Agilent Zorbax Bonus C18 reversed-phase column (50 x 2.1 mm, 5 jt/rn particle size). The column temperature was maintained at 70°C in a column oven. The mobile phase consisted of 80% methanol and 20% 40mM ammonium acetate buffer (pH 5.1) delivered isocratically at a flow of 0.4 mL/min. D12 cyclosporine was the IS. 

Kabra, P.M., Wall, J.H., and Dimson, P. 1987. Automated solid phase extraction and liquid chromatography for assay of cyclosporine in whole blood. Clin Chem. 33 2272. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

If St. John s wort can alter levels of cyclosporin in the blood, might it not also interfere with the action of other medications Recent research indicates that it can. Not surprisingly, the affected drugs are those that, like cyclosporin, are also metabolized by cytochrome enzymes. Protease inhibitors, used in the treatment of hiv infections, are a prime example. Because of the popularity of St. John s wort as an antidepressant and the incidence of depression in patients diagnosed with HIV infections, researchers at the U.S. National Institutes of Health decided to investigate the consequences of using the herbal remedy and the protease inhibitor indinavir concurrently. Doctors prescribe indinavir to prevent the hiv virus... 

As for cyclosporine, its blood concentration is impacted by drugs that act on the CYP3A system. Drugs that inhibit this enzyme will increase its blood concentration and drugs that enhance the activity of CYP3A will decrease the blood concentration of tacrolimus. In combination with cyclosporine, it produces additive renal toxicity. 

D. C. Muddiman, A. I. Gusev, A. Proctor, D. M. Hercules, R. Venkataraman, and W. Diven, Quantitative measurement of cyclosporin A in blood by time-of-flight mass spectrometry, Anal. Chem., 66 (1994) 2362-2368. 

M. Lemaire and J. P. Tillement, Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin in the blood, J. Pharm. Pharmacol. 34 715-718 (1982). 

M. Lemaire, W. M. Partridge, and G. Chaudhuri, Influences of blood components on the tissue uptake indices of cyclosporin in rats, J. Pharmacol. Exp. Ther. 244 740-743 (1988). 

McBride JH, Kim SS, Rodger son DO, Reyes AF, Ota MK. Measurement of cyclosporine by liquid chromatography and three immunoassays in blood from liver, cardiac, and renal transplant recipients. Clin Chem 1992 38 2300-6. 

Cohnan E, Fossler M. Reduction in blood cyclosporine concentrations by orhstat. N Engl J Med 2000 342(15) 1141-2. 

Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am J Nephrol 1985 5(5) 385-7. 

Lorf T, Ramadori G, Ringe B, Schworer H. Pantoprazole does not affect cyclosporin A blood concentration in kidney-transplant patients. Eur J Clin Pharmacol 2000 55(10) 733-5. 

Lustig S, Stern N, Eggena P,Tuck ML, Lee DB. Effect of cyclosporin on blood pressure and renin-aldosterone axis in rats. Am J Physiol 987 253 H1596-H1600. 

Murray BM, Paller MS. Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats. Clin Nephrol 1986 25 Supp11 S37-S39. 

Carvalho MJ, van den Meiracker AH, Boomsma F, Freitas J, Man in t Veld AJ, Costa O, de Freitas AF. Role of sympathetic nervous system in cyclosporine-induced rise in blood pressure. Hypertension 1999 34 102-106. 

Absorption of cyclosporine in the form of Sandimmune is highly variable, ranging from 5% to 40%, Whole-blood concentration correlates with the degree of immunosuppression and toxicity, but there is a poor relationship between dose and blood concentration. A microemulsion form of cyclosporine, Neoral, has more reproducible absorption— averaging 40%—and exhibits better correlation between dose, blood level, and clinical response. In addition to... 

Moyer TP, Post GR, Sterioff S, Anderson CF. Cyclosporine nephrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood. Mayo Clin Proc 1988 63 241-7. 

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