Effects of various absorption enhancers on transport of clodronate through Caco-2 cells

The major disadvantage concerning clinical use of bishosphonate drugs, like clodronate, is their poor and variable absorption after oral administration. The objective of this study was to assess the effects of four different absorption enhancers—palmitoyl carnitine chloride (PCC), N-trimethyl chitosan chloride (TMC), sodium caprate (C10), and ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA)—on the transport of clodronate using Caco-2 cell culture model. The transport experiments were performed in a normal (1.3 mM) and in a minimum-calcium concentration (apically calcium-free medium and basolaterally 100 μM calcium concentration). In the normal calcium concentration, a strong enhancement in clodronate permeation was observed with the enhancers: EGTA (2.5 mM), TMC (1.5% w/v), and PCC (0.2 mM) increased the transport of 1 mM clodronate 190-, 20-, and 10-fold, respectively, and the transport of 10 mM clodronate 130-, 70-, and 35-fold. In the minimum-calcium concentration, the effects of the absorption enhancers on the transport of clodronate were not so potent: TMC, PCC, and EGTA caused 2- to 20-fold enhancement in clodronate permeation whereas C10 (10 mM) was without any effect. According to the results, the permeation of clodronate through Caco-2 cells could be significantly promoted by the absorption enhancers, which cause widening of the tight junctions and, thus, increase the permeability of the paracellular route.