Cyclosporine A, a macrocyclic peptide, is transported by organic anion transporting polypeptide 1B1/1B3 at clinically relevant doses.

Cyclosporine A (CSA) is a large lipophilic cyclic peptide used primarily for the prevention of organ rejection following transplantation. Because of the narrow therapeutic window and variable pharmacokinetics, therapeutic drug monitoring is considered in CSA dosing. Hepatic and intestinal CYP3A-mediated metabolism is known to determine CSA pharmacokinetics and drug-drug interactions; however, the mechanisms governing its entry into hepatocytes are not well understood. Here, we evaluated the hepatic uptake mechanism(s) of CSA using transporter-transfected cell systems and Oatp1a/1b knockout mice. [3H]-CSA exhibited robust organic anion transporting polypeptide (OATP)1B1/1B3-mediated transport, with uptake ratios of up to 4-fold at 10 and 50 nM. OATP1B1/1B3-specific transport was diminished at higher CSA concentrations and in the presence of excess unlabeled ("cold") CSA or the OATP1B inhibitor, rifamycin SV. No transport was apparent via other major hepatic uptake transporters, including Na+-taurocholate cotransporting polypeptide. Intravenous clearance was ∼2.4-fold lower (P < .05) in the Oatp1a/1b knockout mice compared with wild-type mice. Additional transport studies in OATP1B-transfected cells revealed an efflux half-life of up to 110 minutes, suggesting prolonged cell retention. A 30-minute preincubation produced a 3- to 9-fold shift (potentiation) in cold CSA OATP1B IC50 values when using [3H]-CSA as probe substrate. In conclusion, to our knowledge, these studies demonstrate for the first time a specific transport mechanism for cyclosporine uptake in the human liver and suggest that OATP1B1/1B3 has a critical role in its pharmacokinetics. Low uptake and efflux rates may suggest slower dissociation of CSA from OATP1B, leading to the apparent time-dependent inhibition effect in spite of the competitive interaction mechanism. SIGNIFICANCE STATEMENT: The in vitro and in vivo results of this study suggest that organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake plays a significant role in the pharmacokinetics of cyclosporine. Considerations of drug-induced or genotypic modulations in OATP1B activity are, therefore, important in optimizing dosing for this narrow therapeutic index drug. This serves as an example of a macrocyclic peptide involving OATP1B substrate activity at clinically relevant concentrations.