We examined the action mechanisms of enhancers that improve paracellular dr
ug transport. For sodium caprate (C10), the increase in the intracellular c
alcium level was considered to induce the contraction of calmodulin-depende
nt actin filaments, followed by dilation of the paracellular pathway. Altho
ugh decanoylcarnitine (DC) also increased the intracellular calcium level,
the action was independent of calmodulin and thus, the action mechanism of
acylcarnitines was considered to differ from that of C10. Other acylcarniti
nes, lauroylcarnitine (LC) and palmitoylcarnitine (PC) and organic acids, t
artaric acid (TA) and citric acid (CA) decreased the intracellular ATP leve
l and the intracellular pH. From these results, it was considered that one
of the action mechanism of acylcarnitines and organic acids is that the int
racellular acidosis increases the calcium level through the decrease in ATP
levels, followed by opening the tight junction. Membrane dysfunction which
was expected from the above mechanism was assessed by the transport functi
on of electrolytes. Membrane conductance, which was increased by C10, LC an
d PC, returned to the control value during a 3- to 6-h recovery period. On
the other hand, Cl- ion secretion, which was obtained from short-circuit cu
rrent (I-sc), was decreased by these enhancers, but was normalized by C10 b
ut not by LC and PC. Accordingly, C10 can be considered a safer enhancer th
an acylcarnitines. (C) 1999 Elsevier Science B.V. All rights reserved.