Enhanced Oral Delivery of Bisphosphonate by Novel Absorption Enhancers: Improvement of Intestinal Absorption of Alendronate by N-Acyl Amino Acids and N-Acyl Taurates and Their Absorption-Enhancing Mechanisms

Abstract

Bisphosphonates (BPs) are carbon-substituted pyrophosphate analogs that exhibit a high affinity to hydroxyapatite and specifically inhibit bone resorption. Alendronate sodium (sodium 4-amino-1-hydroxybutylidene-1,1-bisphosphonate trihydrate) is a typical BP compound in clinical use. BPs have very low bioavailability, typically <1% after their oral administration, and their intestinal absorption is further reduced by co-administered drugs or food. In this study, we examined the effects of N-acyl amino acids and N-acyl taurates on the small intestinal absorption of alendronate. All N-acyl amino acids and N-acyl taurates increased the small intestinal absorption of alendronate, especially 1% (wt/vol) sodium palmitoyl sarcosinate (PN), which elicited a 14-fold increase. In addition, the absorption-enhancing effects of these enhancers were reversible and they may not cause continuous and irreversible membrane toxicity in the rat small intestine. Furthermore, we examined the absorption-promoting mechanisms of PN and found that it increased the membrane fluidity of the lipid bilayers. In addition, it was found that PN may open the tight junctions by reducing the expression level of claudin-4, which is a major tight junction protein. These findings indicate that these enhancers are useful for promoting the intestinal absorption of alendronate.

Keywords: Caco-2 cells; absorption enhancer; intestinal absorption; membrane transport; tight junction.