Improved Intestinal Permeation of Cyclosporin a by FCIGRL-Modified Tight Junction Modulator in Rats.

Objectives: Cyclosporin A (CsA) is an immunosuppressive drug that is highly effective. CsA, similar to other drugs with limited oral bioavailability due to poor membrane permeability, requires the use of absorption enhancers in its formulations. Phe-Cys-Ile-Gly-Arg-Leu (FCIGRL-OH), a peptide fragment of Zonula occludens toxin (ZOT), has been studied for its potential to enhance drug absorption by regulating intercellular tight junctions. This study aimed to evaluate the effects of four novel modified peptides, which have been substituted or dimerized at the C-terminus or cysteine moiety of FCIGRL-OH, as improved versions of FCIGRL-OH on the intestinal permeation of CsA. Methods: The four modified peptides used were FCIGRL-NH2 (Pep-1), homo-dimer peptides derived from FCIGRL-OH and Pep-1 (Pep-2, Pep-3), and a peptide in which the cysteine in Pep-1 was replaced with N3-substituted dipropionic acid (Pep-4). Pharmacokinetic analysis was performed following intraduodenal administration of CsA with each of four peptides in the presence of levan and benzalkonium chloride (BC) in rats. Results: Results showed that each of Pep-2, Pep-3, and Pep-4 significantly increased intestinal absorption of CsA in the presence of levan and BC. In particular, the area under the curve (AUC0-360min) for CsA was significantly enhanced by 2.01-fold (p < 0.01) and 2.03-fold (p < 0.05) when treated with Pep-3 and Pep-4, respectively, at a dose of 10 mg·kg-1. Additionally, the maximum plasma concentration (Cmax) of CsA increased by 2.46-fold (p < 0.01) with Pep-3 and by 2.37-fold (p < 0.01) with Pep-4. Conclusions: These study findings indicate that Pep-2, particularly Pep-3 and Pep-4, are involved in tight junction opening as novel absorption enhancers for intestinal delivery of CsA.