PEG-metronidazole conjugates: synthesis, in vitro and in vivo properties.
Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.
Bersani
Cinzia
C
Department of Pharmaceutical Sciences, University of Padova, Via F. Marzolo, 5, 35131 Padova, Italy.
Berna
Manuela
M
Pasut
Gianfranco
G
Veronese
Francesco Maria
FM
D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D008795:Metronidazole / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet
D000981:Antiprotozoal Agents; D008795:Metronidazole; D011092:Polyethylene Glycols