Modulation of intestinal permeability of 5-fluorouracil via phospholipid interaction based lipophilic complex designing and pharmacokinetic assessment

Abstract

5-Fluorouracil (5-FU) is a poorly bioavailable anti-tumor drug with impaired permeability function across gut mucosa. To modulate the permeability of 5-FU, a 5-FU-phospholipid based lipophilic complexes was developed. 5-fluorouracil-phospholipid complexes (FUPLCs) complexes were prepared at weight ratios (1:1, 1:2 and 2:1) of phospholipid (PL) and 5-FU using solvent evaporation method. FTIR characterization showed that FUPLCs were formed from molecular interaction held between 5-FU & PL; as change in the vibrational frequencies of PL appeared at 1227, 1085 and 1051 cm⁻¹were shifted to 1224, 1069 and 1037 cm⁻¹ for > P = O, >ONH-, and -NH-OH- respectively. Melting endotherm of 5-FU appeared at 287 °C and was shifted to 278 °C in the complex. XRD pattern of FUPLC was crystalline; and indicates phospholipid (amorphous solid) occupied into crystal lattice of 5-FU. FUPLCs produce distinct conductive species in comparison to 5-FU and allow changes in the electrical conductivity pattern due to changes in the molecular orientations when diluted in Tween 20/ethanol environment. Furthermore, partition coefficient measurement confirmed the lipophilic character of complexes. In vitro drug release studies demonstrated that complexes produce delayed release patterns over 5-FU in phosphate buffer at pH 6.8, HCl buffer at pH 1.2 and distilled water. These variations in drug release patterns could reflect hydrophobic nature of complexes. FUPLC gave higher drug permeability (p < 0.001) across the intestinal sac than the 5-FU solution. P_eff value from FUPLCs (1:1; and 1:2) and 5-FU was 8.0×10⁻⁵ and 4.0×10⁻⁵cm/sec respectively in apical to basolateral direction (A→B). Modulation of drug permeability in FUPLC could relate to the lipophilic character of 5-FU/PL interaction. Pharmacokinetic assessment in the Wistar rat model showed that complex (1:1) produced three-fold enhancement in the AUC(_0-120min) over 5-FU administered orally. Designing lipophilic carriers based on drug/PL interaction produces changes in the 5-FU release and modulates the intestinal permeability and bioavailability. Lipophilic carrier of 5-FU viz. FUPLCs could be employed in the designing of nanoemulsion, (Self-emulsifying drug delivery system) SEDDS or (Self-Nanoemulsifying drug delivery system) SNEDDS system for bioavailability enhancement of BCS class III.

Graphical Abstract

Keywords:

• 5-Fluorouracil
• permeability
• phospholipid
• 5-Fluorouracil-phospholipid complex
• lipophilic carrier

Authors contribution

Anoop Kumar works on research conceptualization and prepares the plan of work, Piyush Kumar Singh Arya works for data acquisition in the laboratory. Amulya Jindal helps in pharmacokinetic activity with Anoop Kumar prepares the statistical data. Anoop Kumar and Piyush Arya drafted the initial draft, Anoop Kumar and Amulya Jindal worked majorly on correction and preparation of final draft. Also, Amulya Jindal and Anoop Kumar worked on revision-received and edited the manuscript.

IAEC ethics approval letter

Study design conducted on animals was approved (MIET/IAEC/CPCSEA/2023/93) by Institutional Animal Ethics Committee (IAEC) of MIET, Meerut-250005, Uttar Pradesh, India.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Required data is already attached in the manuscript and there is not any supplementary data to show.