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

Area of Science:

• Pharmacology
• Drug Delivery
• Biochemistry

Background:

• Cyclosporin A (CsA) is a vital immunosuppressant with limited oral bioavailability due to poor membrane permeability.
• Absorption enhancers are crucial for formulating drugs like CsA with poor oral absorption.
• Phe-Cys-Ile-Gly-Arg-Leu (FCIGRL-OH), a peptide derived from Zonula occludens toxin (ZOT), modulates intercellular tight junctions to improve drug absorption.

Purpose of the Study:

• To evaluate the efficacy of four novel modified peptides (Pep-1, Pep-2, Pep-3, Pep-4) as enhanced versions of FCIGRL-OH.
• To assess the impact of these peptides on the intestinal permeation and absorption of Cyclosporin A (CsA).
• To investigate the potential of modified FCIGRL-OH peptides in improving CsA oral bioavailability.

Main Methods:

• Four modified peptides were synthesized: FCIGRL-NH2 (Pep-1), homo-dimer peptides (Pep-2, Pep-3), and a cysteine-substituted peptide (Pep-4).
• Pharmacokinetic analysis was conducted in rats following intraduodenal administration of CsA combined with each peptide.
• The study involved the co-administration of levan and benzalkonium chloride (BC) with CsA and the peptides.

Main Results:

• Pep-2, Pep-3, and Pep-4 significantly enhanced the intestinal absorption of CsA in the presence of levan and BC.
• Pep-3 and Pep-4 administration resulted in a 2.01-fold and 2.03-fold increase in the area under the curve (AUC0-360min) for CsA, respectively.
• Maximum plasma concentration (Cmax) of CsA increased by 2.46-fold with Pep-3 and 2.37-fold with Pep-4.

Conclusions:

• The novel peptides Pep-2, Pep-3, and Pep-4 act as effective absorption enhancers for intestinal drug delivery.
• Pep-3 and Pep-4 demonstrate significant potential in improving the oral bioavailability of Cyclosporin A (CsA).
• These peptides function by modulating tight junction permeability, facilitating enhanced drug absorption.