However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis. Pharmacokinetics
Ciclosporin is a cyclic peptide of 11 amino acids; it contains a single D-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L, have less than 10% of ciclosporins immunosuppressant activity and are associated with higher kidney toxicity. Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied. Biosynthesis
Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase. The enzyme contains an adenylation domain, a thiolation domain, a condensation domain, and an N-methyltransferase domain. The adenylation domain is responsible for substrate recognition and activation, whereas the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine, and the condensation domain elongates the peptide chain. Cyclosporin synthetase substrates include L-valine, L-leucine, L-alanine, glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine, which is the starting amino acid in the biosynthetic process. With the adenylation domain, cyclosporin synthetase generates the acyl-adenylated amino acids, then covalently binds the amino acid to phosphopantetheine through a thioester linkage. Some of the amino acid substrates become N-methylated by S-adenosyl methionine. The cyclization step releases cyclosporin from the enzyme. Amino acids such as D-Ala and butenyl-methyl-L-threonine (Bmt) indicate cyclosporin synthetase requires the action of other enzymes. The racemization of L-Ala to D-Ala by alanine racemase is pyridoxal phosphate-dependent.
Calne and colleagues at the University of Cambridge, and in liver transplants performed by Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on 9 March 1980, was a 28-year-old woman. In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983. Society and culture
Name
The natural product was named cyclosporin by the German-speaking scientists who first isolated it and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs, the y was replaced with i so that the INN for the medication is spelled ciclosporin.Ciclosporin is the INN and the British Approved Name (BAN), while cyclosporine is the United States Adopted Name (USAN) and cyclosporin is a former BAN. Available forms
Ciclosporin exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the medication have been developed for oral administration and for injection. Ciclosporin was originally brought to market by Sandoz (now Novartis), under the brand name Sandimmune, which is available as soft gelatin capsules, an oral solution, and a formulation for intravenous administration. These are all nonaqueous compositions. A newer microemulsion, orally-administered formulation, Neoral, is available as a solution and as soft gelatin capsules. The Neoral compositions are designed to form microemulsions in contact with water.Generic ciclosporin preparations have been marketed under various trade names, including Cicloral (Sandoz/Hexal), Gengraf (Abbott) and Deximune (Dexcel Pharma). Since 2002, a topical emulsion of ciclosporin for treating inflammation caused by keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the trade name Restasis.