A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Cyclosporine is produced as a metabolite by the fungus species Cordyceps militaris. (From Martindale, The Extra Pharmacopoeia, 30th ed).
The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. The extent of absorption is dependent on the individual patient, the patient population, and the formulation. The absolute bioavailability of cyclosproine administered as Sandimmune™ is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The cyclosporine capsules and oral solution are bioequivalent. The time of peak blood concentrations (Tmax) following oral administration of cyclosporine [modified] ranged from 1.5 - 2.0 hours.
Mechanism of Toxicity
Cyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.
Metabolism
Hepatic, extensively metabolized by the cytochrome P450 3A enzyme system in the liver. It is also metabolized in the gastrointestinal tract and kidney to a lesser degree. The metabolites are significantly less potent than the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.
Route of Elimination: Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Only 0.1% of the dose is excreted in the urine as unchanged drug.
Half Life: Biphasic and variable, approximately 7 hours (range 7 to 19 hours) in children and approximately 19 hours (range 10 to 27 hours) in adults.
Toxicity Values
The oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
For treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
Minimum Risk Level
Not Available
Health Effects
Not Available
Symptoms
The oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
Hans Dietl, “Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and a process for its production.” U.S. Patent US5527537, issued October, 1990.
