Physiological mechanism for enhancement of paracellular drug transport

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.