Molecular Weight-Dependent Paracellular Transport of Fluorescent Model Compounds Induced by Palmitoylcarnitine Chloride across the Human Intestinal Epithelial Cell Line Caco-2

Abstract

Long-chain acylcarnitines, such as palmitoylcarnitine chloride (PCC), are endogenous compounds which have been shown to increase intestinal transport of small hydrophilic compounds (including some pharmaceutical agents) through the paracellular pathway. However, the size range of the compounds whose absorption can be improved by PCC has not been fully investigated. In the present study, we systematically examined the effect of PCC on the transport rate of a series of hydrophilic fluorescent model compounds of varying molecular weights (0.3–71.2kD) across cultured monolayers of the human intestinal epithelial cells Caco-2. Mucosal addition of 100 or 200 μM PCC resulted in comparable time-dependent decreases in the transepithelial electric resistance (T_1/2, ∼15 min). PCC addition induced a striking increase in the transport of sodium fluorescein (Flu-Na; 0.3 kD) and a slight or moderate increase in transports of fluorescent compounds of 0.6-11 kD. The effect of PCC on transport of compounds with molecular weights of ≥17kD appeared to be negligible. Examination by confocal laser scanning microscopy clearly revealed dilated paracellular spaces in Caco-2 monolayers which had been mucosally pretreated with PCC, confirming that PCC increases intestinal permeability by opening a paracellular transport pathway. Our results suggest that PCC is particularly effective in enhancing intestinal absorption of small hydrophilic compound like Flu-Na and may also have limited use in promoting the transport of compounds of ≤10kD.

Key Words:

• Acylcarnitines
• Caco-2
• Confocal laser scanning microscopy
• Intestinal transport
• Permeation-enhancing agents
• TEER