title: Activity-bioavailability balance in oral drug development for a selected group of 6-fluoroquinolones.
abstract: A nomogram is proposed to select the best candidate in drug development studies with quinolones and is intended to substitute other possible models. The nomogram is referred to as an activity-bioavailability balance (ABB) because it includes the following two criteria: ABB = [(1/gm MIC drug candidate)/ (1/gm MIC ciprofloxacin)].[(F(calc) drug candidate)/( F(calc) ciproflaxacin)]. The in vitro activity of a group of 4'N-alkyl-ciprofloxacin derivatives was determined together with that of ciprofloxacin, initially against some reference strains and subsequently against 159 clinical isolates of eight selected species. The inverse of the geometric mean of the lowest concentration of drug at which the original inoculum was reduced to no more than two colonies (1/gm MIC), as an antimicrobial activity parameter, and the absolute oral bioavailability index (F(calc)), as predicted from in situ intestinal absorption rate constants, were used for calculation of the ABB values, which ranged from 0.1 to 17 for the species and compounds tested. Ciprofloxacin was the best candidate only against Escherichia coli, whereas 4'N-methyl- and/or 4'N-ethyl-ciprofloxacin showed better or much better ABB values than the model drug, and can be selected as potential drug candidates against the remaining clinical strains. The procedure described could be a useful technique for further drug development studies.
authors.affiliation: Unit of Experimental Bacteriology Research Center, La Fe Hospital, 46009 Valencia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Taléns-Visconti
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Garrigues
authors.forename: Emilia
authors.initials: E
authors.lastname: Cantón
authors.forename: Joan
authors.initials: J
authors.lastname: Freixas
authors.forename: Adela
authors.initials: A
authors.lastname: Martín-Villodre
authors.forename: José M
authors.initials: JM
authors.lastname: Plá-Delfina
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D024841:Fluoroquinolones; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D051381:Rats; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones