title: Determination of lipophilicity of two quinolone antibacterials, ciprofloxacin and grepafloxacin, in the protonation equilibrium.
abstract: The objective of this study was to compare protonation equilibrium and lipophilicity of two quinolone antibacterials, grepafloxacin (GPFX) and ciprofloxacin (CPFX), in order to give an insight into effects on the physicochemical properties by slight structural motifs. The protonation equilibrium was investigated by a spectrophotometry. Macro- and micro-dissociation constants were simultaneously determined, based on nonlinear regression analysis using the MULTI program, and then microspecies distribution could be described accordingly. Zwitterionic microspecies predominated at isoelectrical point (pI) for both drugs, and the concentration ratio of neutral to zwitterionic forms was near 4-fold greater for GPFX than that for CPFX. The apparent partition coefficient (D(O/B,pH)) versus pH profiles had the shape of a parabolic curve in an n-octanol/buffer system, and reached the maximum around pI for both, respectively. Moreover, two introduced methyl groups in GPFX increased not only intrinsic lipophilicity but also neutral microspecies fraction relative to CPFX, and D(O/B,pH) of GPFX was consequently far higher than that of CPFX. The results emphasized that there were significant differences in protonation equilibrium and lipophilicity between GPFX and CPFX, which conduced to explaining their different behavior in terms of antibacterial activities and pharmacokinetics.
authors.affiliation: Department of Pharmaceutics, Hokkaido College of Pharmacy, 7-1 Katsuraoka-cho, Otaru-city, Hokkaido 047-0264, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.forename: Shigeko
authors.initials: S
authors.lastname: Sakai
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tauchi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
authors.forename: Jimin
authors.initials: J
authors.lastname: Chen
authors.forename: Ruhua
authors.initials: R
authors.lastname: Zhang
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morimoto
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry*; D002939:Ciprofloxacin / Q000737:chemistry*; D024841:Fluoroquinolones; D010879:Piperazines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D010879:Piperazines; D002939:Ciprofloxacin; C075375:grepafloxacin