title: Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide.
abstract: The mechanisms of reduction in absorption of levofloxacin (LVFX) by coadministration of aluminum hydroxide were studied. The partition coefficient of LVFX (0.1 mM) between chloroform and phosphate buffer (pH 5.0) was reduced by 60 to 70% with the addition of metal ions such as Cu2+, Al3+, and Fe2+ (0.8 mM), which indicated the formation of LVFX-metal ion chelates. However, there was no significant difference in absorption from rat intestine between the synthetic LVFX-Al3+ (1:1) chelate (6.75 mM) and LVFX (6.75 mM) in an in situ recirculation experiment. On the other hand, Al(NO3)3 (1.5 mM) significantly inhibited the absorption of LVFX (1.5 mM) by 20% of the control in the in situ ligated loop experiment, in which partial precipitation of aluminum hydroxide was observed in the dosing solution. Data for adsorption of LVFX and ofloxacin (OFLX) from aqueous solution by aluminum hydroxide were shown to fit Langmuir plots, and the adsorptive capacities (rmax) and the K values were 7.0 mg/g and 1.77 x 10(4) M-1 for LVFX and 7.4 mg/g and 1.42 x 10(4) M-1 for OFLX, respectively. The rate of adsorption of several quinolones (50 microM) onto aluminum hydroxide (2.5 mg/ml) followed the order norfloxacin (NFLX) (72.0%) > enoxacin (ENX) (61.0%) > OFLX (47.2%) approximately LVFX (48.1%). The elution rate of adsorbed quinolones with water followed the rank order LVFX (17.9%) approximately OFLX (20.9%) approximately ENX (18.3%) > NFLX (11.9%). These results strongly suggest that adsorption of quinolones by aluminum hydroxide reprecipitated in the small intestine would play an important role in the reduced bioavailability of quinolones after coadministration with aluminum-containing antacids.
authors.affiliation: Developmental Research Laboratories, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Kurata
authors.forename: C
authors.initials: C
authors.lastname: Fujisawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ohshima
authors.forename: H
authors.initials: H
authors.lastname: Aoki
authors.forename: O
authors.initials: O
authors.lastname: Okazaki
authors.forename: H
authors.initials: H
authors.lastname: Hakusui
mesh_terms: D000536:Aluminum Hydroxide / Q000494:pharmacology*; D000818:Animals; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002725:Chloroform; D004347:Drug Interactions; D015365:Enoxacin / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects*; D064704:Levofloxacin; D008297:Male; D009643:Norfloxacin / Q000737:chemistry / Q000493:pharmacokinetics; D015242:Ofloxacin / Q000737:chemistry / Q000493:pharmacokinetics*; D010710:Phosphates; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002021:Buffers; D010710:Phosphates; D015365:Enoxacin; D000536:Aluminum Hydroxide; D064704:Levofloxacin; D002725:Chloroform; D015242:Ofloxacin; D009643:Norfloxacin