Yoshihiro Furuya

Increased systemic availability of cyclosporin A by formulation design: pharmacokinetic consideration on its transport

Abstract The systemic availability of cyclosporin A (CyA) from two different oral formulations was investigated in rats in relation to the lymphatic transport of CyA. The two test oral CyA formulations were a well-solubilized solution with a pharmaceutical additive, polyoxy 60 caster oil (HCO-60), and an olive oil formation. Each formulation was administered orally to two groups of 4 rats. After oral administration of the HCO-60 formulation, 7 mg/kg, the peak plasma CyA level and the area under the curve (AUC) were 1.5 times higher than obtained from the olive oil formulation. To clarify the contribution of the two absorption routes, portal and lymphatic, on the systemic availability of CyA, a pharmacokinetic study was performed by administering CyA to two more groups of 3 rats by two different administration routes, intraportal (i.p.) infusion and intravenous (i.v.) injection. The mean AUC after i.p. infusion, 7 mg/kg, was 11.32 ± 0.85(S.E.M.) μg · h/ml and after i.v. injection, 3.5 mg/kg, was 8.74 ± 0.85 (S.E.M.) μg · h/ml. By analyzing these results with a physiologic pharmacokinetic model containing the liver and gastrointestinal (GI) tissue as metabolic eliminating organs for CyA, the increased systemic availability of CyA by formulation design was revealed to be due to increased absorption from the GI tract and the main transport route after being absorbed into the GI cells was revealed to be the portal venous system.