Improving Eflornithine Oral Bioavailability and Brain Uptake by Modulating Intercellular Junctions With an E-cadherin...

Area of Science:

• Pharmacology
• Drug Delivery
• Neuroscience

Background:

• Eflornithine is crucial for treating human African trypanosomiasis but suffers from poor oral absorption and limited blood-brain barrier penetration.
• Current treatment requires complex intravenous infusions, impacting patient compliance and accessibility.
• Developing alternative delivery methods is essential to improve therapeutic outcomes.

Purpose of the Study:

• To evaluate the potential of the E-cadherin peptide HAV6 in enhancing eflornithine's oral bioavailability and brain delivery.
• To assess the stability and efficacy of HAV6 in improving drug permeation across biological barriers.

Main Methods:

• Investigated eflornithine metabolism and transporter interactions.
• Assessed peptide stability in simulated physiological conditions (gastric fluid, plasma).
• Utilized cell monolayer models (MDCK, Caco-2) and an in situ rat brain perfusion model to measure drug permeability.
• Conducted pharmacokinetic studies in rats with coadministered eflornithine and HAV6.

Main Results:

• Eflornithine showed no significant metabolism or efflux transporter activity.
• HAV6 demonstrated stability and significantly increased eflornithine permeability across cell monolayers (up to 8.5-fold).
• In vivo studies showed HAV6 increased brain eflornithine concentrations (up to 4.9-fold) and oral bioavailability (from 38% to 54%).

Conclusions:

• Coadministration with HAV6 substantially improves eflornithine's oral bioavailability and brain penetration.
• HAV6 offers a promising strategy for developing improved oral or simplified intravenous formulations of eflornithine.
• This approach holds potential for enhancing treatment efficacy for human African trypanosomiasis.