(Acyloxy)alkyl carbamate prodrugs of norfloxacin.
As a new prodrug approach to norfloxacin (NFLX) we prepared the acetoxyalkyl carbamates of the type NFLX-CO-OCHR-OAc by the reaction of sodium or mercuric acetate on NFLX alpha-chloroalkyl carbamates. These produrgs did not have the bitter taste of NFLX. In vitro, the acetoxyethyl carbamate exhibited activity only against Staphylococcus spp. and was inactive against Gram-negative organisms. However, in the presence of serum and intestinal homogenate, esterase-catalyzed hydrolysis of the ester bond in these modified carbamates led to a cascade reaction resulting in the rapid regeneration of NFLX. At high oral doses of the prodrug, the acetaldehyde produced as a side product in the breakdown of the promoiety caused a slight decrease in alcohol metabolism in a mouse model. The bioavailability of NFLX from the acetoxyethyl carbamate was lower compared to an equivalent dose of NFLX when given as an oral suspension in rhesus monkeys, presumably because of the lower aqueous solubility of the prodrug.
Alexander
J
J
INTERx Research Corporation, Merck Sharp and Dohme Research Laboratories, Lawrence, Kansas 66047.
Fromtling
R A
RA
Bland
J A
JA
Pelak
B A
BA
Gilfillan
E C
EC
D000818:Animals; D001419:Bacteria / Q000187:drug effects; D001682:Biological Availability; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008253:Macaca mulatta; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009643:Norfloxacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002219:Carbamates; D011355:Prodrugs; D009643:Norfloxacin