title: Synthesis and evaluation of sulfate conjugated metronidazole as a colon-specific prodrug of metronidazole.
abstract: For an effort to improve therapeutic property of metronidazole (MTZ) which is a drug of choice for protozoal infections such as luminal amoebiasis, sulfate conjugated metronidazole (MTZS) was prepared and evaluated as a colon-specific prodrug of MTZ. The apparent partition coefficient of MTZ was greatly reduced by the sulfate conjugation. While (bio)chemically stable in the contents of the upper intestine, MTZS was rapidly cleaved to liberate MTZ on incubation with the cecal contents of rats. MTZ liberated from MTZS metabolized quickly at least partly by a microbial nitroreductase, suggesting the relevance of the metabolism to bioactivation of MTZ for antimicrobial action. Consistent with the hypothesis, MTZS elicited antibacterial activity in the cecal contents, which was as potent as free MTZ. The systemic absorption of MTZS was very low after oral administration of MTZS. In parallel with this, whereas MTZ disappeared mostly during the transit of the proximal small intestine, a substantial amount of MTZS remained in the small intestine, moving down to the large intestine where it metabolized rapidly. In addition to the efficient colonic delivery of MTZS, MTZS markedly reduced the systemic absorption of MTZ. Taken together, MTZS may be a potential colon-specific prodrug of MTZ which possesses improved therapeutic and toxicological properties.
authors: Laboratory of Biomedicinal/Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Korea.
authors: Hyunjeong
authors: H
authors: Kim
authors: Yonghyun
authors: Y
authors: Lee
authors: Hansun
authors: H
authors: Yoo
authors: Jihye
authors: J
authors: Kim
authors: Hyesik
authors: H
authors: Kong
authors: Jeong-Hyun
authors: JH
authors: Yoon
authors: Yunjin
authors: Y
authors: Jung
authors: Young Mi
authors: YM
authors: Kim
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002432:Cecum / Q000382:microbiology; D003106:Colon / Q000737:chemistry* / Q000378:metabolism; D003108:Colonic Diseases / Q000188:drug therapy; D016503:Drug Delivery Systems; D004355:Drug Stability; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D005766:Gastrointestinal Contents / Q000201:enzymology / Q000382:microbiology; D007408:Intestinal Absorption; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008297:Male; D008795:Metronidazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D009601:Nitroreductases / Q000378:metabolism; D010949:Plasma / Q000737:chemistry / Q000201:enzymology; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D011355:Prodrugs; D008795:Metronidazole; D009601:Nitroreductases