文摘

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.