Synthesis and properties of dextran-nalidixic acid ester as a colon-specific prodrug of nalidixic acid.
Dextran-nalidixic acid ester (dextran-NA) with a varied degree of substitution (DS) was synthesized as a colon-specific prodrug of nalidixic acid (NA). Solubility in water (mg/ml) of dextran-NA with DS (mg NA/100 mg dextran-NA) of 7, 19, or 32 was 57.57 (equivalent to 4.00 mg NA/ml), 0.53 (equivalent to 0.10 mg NA/ml), or 0.03 (equivalent to 0.01 mg NA/ml), respectively, and that for NA was 0.03 at 25 degrees C. To ensure the chemical stability of dextran-NA at conditions similar to those of the stomach and small intestine, dextran-NA was placed in a solution of pH 1.2 hydrochloric acid buffer or pH 6.8 phosphate buffer and incubated at 37 degrees C; no NA was detected during the 6 h of the incubation period, which indicated that dextran-NA might be chemically stable during the transit through the gastrointestinal tract. Degree of depolymerization (%) by dextranase determined by the 2,4-dinitrosalicylic acid (DNS) method at 37 degrees C for dextran-NA with DS of 7, 19, or 32 was 81, 68, or 8, respectively, in 8 h, and that for dextran was 91. When dextran-NA (equivalent to 50 microg of NA) with a DS of 7 or 17 was incubated with cecal contents (100 mg) of rats at 37 degrees C, the extent of NA released in 24 h was 41% or 32% of the dose, respectively. NA was not liberated from the incubation of dextran-NA with the homogenate of tissue and contents of the small intestine.
Lee
J S
JS
College of Pharmacy, Pusan National University, Korea.
Jung
Y J
YJ
Doh
M J
MJ
Kim
Y M
YM
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry; D003106:Colon / Q000187:drug effects*; D046508:Culture Techniques; D003911:Dextrans / Q000138:chemical synthesis* / Q000737:chemistry; D016503:Drug Delivery Systems; D004952:Esters; D006851:Hydrochloric Acid; D006863:Hydrogen-Ion Concentration; D008297:Male; D009268:Nalidixic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000890:Anti-Infective Agents; D000925:Anticoagulants; D003911:Dextrans; D004952:Esters; D011355:Prodrugs; D009268:Nalidixic Acid; D006851:Hydrochloric Acid