Recent advances in cyclosporine pharmacokinetics.

Although cyclosporine has been in clinical use for more than a decade, many questions persist concerning its pharmacokinetics. Gastric emptying, bile acids, and gastrointestinal motility can influence drug absorption after oral administration, but the relative importance of each of these factors and their interactions as determinants of absorption are not clear. The fraction unbound in plasma has been determined in several studies and may be associated with clinical effects. Biochemical and molecular studies have identified the specific cytochrome P-450 enzymes that metabolize cyclosporine to its primary metabolites. The drug's basic pharmacokinetic profile has been defined and many factors have been identified that can influence clearance, such as age, hepatic function, hematocrit, and lipoprotein concentrations. With the development of sensitive and specific analytical methods, many new cyclosporine metabolites have been identified in humans. The major metabolites are present in relatively high concentrations in human blood and have some immunosuppressive activity in vitro, but their contribution to in vivo immunosuppression is not clear.