title: Ionic complex of risedronate with positively charged deoxycholic acid derivative: evaluation of physicochemical properties and enhancement of intestinal absorption in rats.
abstract: Risedronate is widely used clinically to treat osteoporosis, Paget's disease, hypercalcemia, bone metastasis, and multiple myeloma. However, its oral efficacy is restricted due to its low bioavailability and severe gastrointestinal adverse effects. This study was designed to evaluate the effect of deoxycholic acid derivatives on the permeability and oral bioavailability of risedronate by increasing its lipophilicity and affinity to bile transporters. We synthesized two bile acid derivatives, N(α)-deoxycholyl-L-lysyl-methylester (DCK) and N(α)-deoxycholyl-L-lysyl-hydroxide (HDCK) as oral absorption enhancers. After ionic complex formation with the bile acid derivatives, the complexes were characterized by powder X-ray diffraction. Their artificial membrane permeabilities and bioavailabilities in rats were investigated in comparison with pure risedronate. Complex formation with DCK or HDCK demonstrated that risedronate existed in an amorphous form in the complex. A physical complex of risedronate with DCK enhanced the apparent membrane permeability of risedronate significantly but pure risedronate was not permeable. An in vivo study revealed that the C max and AUClast of risedronate/DCK (1:2) complex were 1.92- and 2.64-fold higher than those of pure risedronate, respectively. Thus, the risedronate/DCK complex can improve the oral absorption of risedronate and patient compliance by reducing dose frequency and adverse reactions.
authors.affiliation: Natural Medicine Research Institute, College of Pharmacy, Mokpo National University, 1666 Youngsan-ro, Cheonggye-myeon, Muan-gun, Jeonnam, 534-729, Republic of Korea, jwpark@mokpo.ac.kr.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000818:Animals; D001682:Biological Availability; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000378:metabolism; D003840:Deoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D012968:Etidronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects*; D007477:Ions; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008567:Membranes, Artificial; D015394:Molecular Structure; D010539:Permeability; D017207:Rats, Sprague-Dawley; D000068296:Risedronic Acid; D012995:Solubility; D013499:Surface Properties; D013997:Time Factors
chemical_list: D050071:Bone Density Conservation Agents; D002352:Carrier Proteins; D004337:Drug Carriers; D007477:Ions; D008562:Membrane Glycoproteins; D008567:Membranes, Artificial; C037643:bile acid binding proteins; D003840:Deoxycholic Acid; D000068296:Risedronic Acid; D012968:Etidronic Acid