IN-VITRO AND IN-VIVO ANALYSIS OF THE MECHANISM OF ABSORPTION ENHANCEMENT BY PALMITOYLCARNITINE

Long-chain acylcarnitines (12-18 carbon fatty acid esters) dramaticall y enhance the absorption of hydrophilic drugs across intestinal mucosa without altering the morphology of the epithelium. The mechanism unde rlying these effects was studied using the colon carcinoma cell line C aco-2. Caco-2 monolayers treated with 0.2 mM palmitoylcarnitine (PCC) show dramatic increases in the transport of hydrophilic markers. This enhanced transport coincides with a rapid drop in transepithelial elec trical resistance (TER). The drop in TER is initiated within the first minute after PCC addition and continues for approximately 20 min to a 70 to 85% drop of the initial TER values. This effect is reversible a fter removing the PCC and does not appear to involve lysis of the apic al membrane. Instead PCC's effect appears to be due to loosening of ti ght junctions as indicated by the accumulation of fluorescent dextrans and the electron dense marker lanthanum nitrate in paracellular space s. Moreover transmission electron microscopy and freeze fracture elect ron microscopy indicate that PCC produces significant structural alter ations to tight junctions. In contrast to many other tight junction di srupting agents, PCC effects appear to be Ca++-independent and PCC doe s not induce significant disruption of actin filament distribution in Caco-2 cells.