US EPA

1315761 

Journal Article 

Metronidazole twin ester prodrugs. Part 2. Nonidentical twin esters of metronidazole and some antiprotozoal halogenated hydroxyquinoline derivatives 

Aboul-Fadl, T; Mahfouz, NM 

1998 

1 

Scientia Pharmaceutica
ISSN: 0036-8709 

IPA/00/1190481 

Pharm 

REF 19 

309-324 

eng 

IPA COPYRIGHT: ASHP The synthesis, prodrug suitability, lipophilic properties, chemical stability, and in vitro and in vivo enzymatic hydrolysis of the following 4 nonidentical twin ester prodrugs by linking metronidazole and some antiprotozoal halogenated 8-hydroxyquinoline derivatives are reported: 1-(5-chloro-7-iodoquinolin-8-yl)-4-(2-(2-methyl-5-nitro-1H-imidazolyl)ethyl)butandioate (I), 1-(5,7-diiodoquinolin-8-yl)-4-(2-(2-methyl-5-nitro-1H-imidazolyl)ethyl)butandioate, 1-(5-chloro-7-iodoquinolin-8-yl)-2-(2-(2-methyl-5-nitro-1H-imidazolyl)ethyl)phthalate, and 1-(5,7-diiodoquinolin-8-yl)-2-(2-(2-methyl-5-nitro-1H-imidazolyl)ethyl)phthalate. The prodrugs showed enhanced lipophilicity compared with the parent drugs. Hydrolysis kinetics indicated quantitative release of pane drugs in a 2-step reaction. Twin esters were adequately stable in aqueous buffer solutions. Bioavailability studies in rabbits of I showed that the plasma level of released metronidazole is higher than that resulting from a physical combination. A considerable amount of 5-chloro-7-iodo-8-hydroxyquinoline was detected in plasma. however, no measurable concentration of the quinoline derivative was observed in rabbit plasma from the physical mixture. 

1-(5-Chloro-7-iodoquinolin-8-yl)-4-(2-(2-methyl-5-nitro-1H-imidazolyl)ethyl)butandioate; prodrugs; synthesis; 1-(5; 1-(5-Chloro-7-iodoquinolin-8-yl)-2-(2-(2-methyl-5-nitro-1H-imidazolyl)ethyl)phthalate; 1-(5; Methotrexate; Drugs; latentiated; Anti-infective agents; methotrexate(Anti-infective agents; Lipophilicity; methotrexate derivatives; Esters; Stability; Hydrolysis; Drugs; Blood levels; Kinetics; Release