title: 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.
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Yuka
authors: Y
authors: Nakaya
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Mayu
authors: M
authors: Takaya
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Yuta
authors: Y
authors: Hinatsu
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Tammam
authors: T
authors: Alama
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Kosuke
authors: K
authors: Kusamori
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Hidemasa
authors: H
authors: Katsumi
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan.
authors: Toshiyasu
authors: T
authors: Sakane
authors: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8414, Japan. Electronic address: yamamoto@mb.kyoto-phu.ac.jp.
authors: Akira
authors: A
authors: Yamamoto
mesh_terms: D000284:Administration, Oral; D019386:Alendronate / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D000596:Amino Acids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D004164:Diphosphonates / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D051381:Rats
chemical_list: D000596:Amino Acids; D004164:Diphosphonates; D019386:Alendronate
keywords: Caco-2 cells; absorption enhancer; intestinal absorption; membrane transport; tight junction