Cyclosporin clinical pharmacokinetics.

Cyclosporin is a powerful immunosuppressive drug used in transplantation medicine and to treat autoimmune diseases. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Cyclosporin is extensively metabolised in the liver by the cytochrome P450 3A system, which is subject to considerable interindividual variation. Distribution of cyclosporin depends not only on physicochemical characteristics, but also on biological carriers such as lipoproteins and erythrocytes in blood. Cyclophilin, a binding protein for cyclosporin, influences distribution of cyclosporin in the body. Despite its lipophilicity, cyclosporin does not appear in the brain. The distribution of metabolites in the body can differ from that of cyclosporin itself. Elimination of the drug is mainly via the bile as metabolites, other routes not being very important. Pharmacokinetic parameters of cyclosporin are highly variable and depend on factors such as age, the physical condition of the patient, type of organ transplant or comedication. Renal side effects of cyclosporin are dose-related, but the influence of the dosage regimen has not been thoroughly investigated. An important factor in the reported variability is the different analytical methods used. Following the recommendations of recent consensus documents to monitor blood concentrations, this source of variability may diminish in the future. Several metabolites are reported as having less immunosuppressive activity than the parent drug. Metabolites with renal side effects have been reported. These and other effects of metabolites have not been clearly defined in the literature, presumably because of the highly variable activity of cyclosporin-metabolising liver enzymes and the paucity of data available on metabolite pharmacokinetics. The therapeutic range and dosage of cyclosporin are therefore highly dependent on many individual parameters in patients. Dosages of less than 5 mg/kg/day, however, rarely cause renal side effects. Further studies to correlate the clinical pharmacokinetics of metabolites with their activity and adverse effects are needed.