Norfloxacin interaction with antacids and minerals.

Campbell, Norman R.C.; Kara, M.; Hasinoff, Brian B.; Haddara, Wael; McKay, Donald W.

doi:10.1111/j.1365-2125.1992.tb04010.x

Cited by 51 publications

(33 citation statements)

References 6 publications

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“…2). These results seem to suggest that the binding of the Al + ion to the 4-keto-and 3-carboxyl-groups of quinolones to form nonabsorbable chelates would be responsible for the reduced absorption of quinolones (4,10,17,19,25).…”

Section: Discussionmentioning

confidence: 88%

“…The formation of nonabsorbable chelates has been suggested as the possible mechanism responsible for the decrease in absorption of some quinolones in the presence of these cations (4,10,17,19,25). However, the magnitude of the decrease in bioavailability varied significantly among the quinolones (13), in spite of their similar stability constants for metal chelate (19).…”

Section: Discussionmentioning

confidence: 99%

“…The bioavailability of quinolone antimicrobial agents including LVFX has been shown to be less when they are ingested with antacids or mineral preparations (13,24), and the binding of metal ions contained in these preparations to the 4-keto-and 3-carboxyl-groups of quinolones to form nonabsorbable chelates has been suggested as the possible mechanism responsible for the reduced absorption of quinolones (4,10,17,19,25). However, attempts to relate the magnitude of reduction in bioavailability by antacids to chemical structures of quinolones or to chelate formation constants have been generally unsuccessful, and the mechanism remains to be elucidated.…”

Section: Levofloxacin (Lvfx) (-)-(S)-9-fluoro-23-dihydro-3-methyl-1mentioning

confidence: 99%

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Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Tanaka¹,

Kurata²,

Fujisawa³

et al. 1993

Antimicrob Agents Chemother

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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 Cu2e, A13+, 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-AI3+ (1:1) chelate (6.75 mM) and LVFX (6.75 mM) in an in situ recirculation experiment. On the other hand, AM(NO3)3 (1.5 mM) significantly inhibited the absorption of LVFX (1.5 mM) by 20%o 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 (r.,) and the K values were 7.0 mg/g and 1.77 x 14 M-1 for LVFX and 7.4 mglg and 1.42 x 104 M'1 for OFLX, respectively. The rate of adsorption of several quinolones (50 ,uM) onto aluminum hydroxide (2.5 mg/ml) followed the order norfloxacin (NFLX) (72.01%) > enoxacin (ENX) (61.0%) > OFLX (47.2%) LVFX (48.1%). The elution rate of adsorbed quinolones with water followed the rank order LVFX (17.9%) OFLX (20.9%) ENX (18.3%) > NFLX (11.91%). 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. Levofloxacin (LVFX), (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate, is a new quinolone antimicrobial agent which exhibits broad-spectrum in vitro bactericidal activities against gram-positive and gramnegative aerobes (8,29). LVFX is the more antibacterially active optical isomer of racemic ofloxacin (OFLX) (8).The bioavailability of quinolone antimicrobial agents including LVFX has been shown to be less when they are ingested with antacids or mineral preparations (13,24), and the binding of metal ions contained in these preparations to the 4-keto-and 3-carboxyl-groups of quinolones to form nonabsorbable chelates has been suggested as the possible mechanism responsible for the reduced absorption of quinolones (4,10,17,19,25). However, attempts to relate the magnitude of reduction in bioavailability by antacids to chemical structures of quinolones or to chelate formation constants have been generally unsuccessful, and the mechanism remains to be elucidated.For the present paper, we studied the mechanisms of pharmacokinetic interaction of LVFX with aluminum hydroxide. The influence of metal ions on the partition coefficient of LVFX between chloroform and phosphate buffer and the adsorptive characteristics of various quinolones such as LVFX, OFLX, enoxacin (ENX), and norfloxacin (NFLX) on the surface ...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Levofloxacin (Lvfx) (-)-(S)-9-fluoro-23-dihydro-3-methyl-1mentioning

confidence: 99%

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Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Tanaka¹,

Kurata²,

Fujisawa³

et al. 1993

Antimicrob Agents Chemother

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“…Also, single doses of ferrous sulfate significantly reduce norfloxacin bioavailability (3). It is generally accepted, therefore, that most multivalent cations decrease the oral bioavailability of the fluoroquinolones (11).…”

mentioning

confidence: 99%

“…Bismuth subsalicylate decreases the bioavailability of tetracyclines significantly, and recommendations have been made for separation of the dosing times for these two medications (1, 4). However, preliminary studies evaluating the interaction of bismuth salts on norfloxacin and ciprofloxacin absorption have demonstrated only minor reductions in fluoroquinolone bioavailability (3,18). These data are in distinct contrast to those observed when ciprofloxacin is administered concurrently with other trivalent cations, such as aluminum.…”

mentioning

confidence: 99%

Effect of bismuth subsalicylate on ciprofloxacin bioavailability

Rambout¹,

Sahai²,

Gallicano³

et al. 1994

Antimicrob Agents Chemother

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A single oral dose of 528 mg of bismuth subsalicylate (30 ml of Pepto-Bismol) had no significant elect on the plasma pharmacokinetics of a single oral dose of 750 mg of ciprofloxacin administered to 12 healthy volunteers (six men and six women). These results suggest that ciprofloxacin bioavailability will not be significantly decreased by single doses of bismuth subsalicylate when the two medications are administered simultaneously.Development of the fluoroquinolones has allowed oral treatment of serious infections which until a few years ago required parenteral therapy (8). Although many of these agents are absorbed well from the gastrointestinal tract, their bioavailability is reduced significantly when administered with antacids containing di-and trivalent metal cations (10,12,16,17). This has resulted in therapeutic failure in at least one instance (11). The exact mechanism of this interaction has not been elucidated fully, although complexation with the metal ions (13-15) and adsorption to the antacids (19, 20) are suggested mechanisms.Bismuth, a heavy metal, can exist as a trivalent cation. Bismuth subsalicylate (Pepto-Bismol) is commonly used for the symptomatic treatment and prevention of a variety of gastrointestinal disorders. Bismuth subsalicylate decreases the bioavailability of tetracyclines significantly, and recommendations have been made for separation of the dosing times for these two medications (1, 4). However, preliminary studies evaluating the interaction of bismuth salts on norfloxacin and ciprofloxacin absorption have demonstrated only minor reductions in fluoroquinolone bioavailability (3,18). These data are in distinct contrast to those observed when ciprofloxacin is administered concurrently with other trivalent cations, such as aluminum. Because patients are likely to receive bismuthcontaining compounds concurrently with fluoroquinolones, among which ciprofloxacin is well established, this study was conducted to determine the effect of a single dose of bismuth subsalicylate on ciprofloxacin absorption in healthy volunteers.This study was approved by the Human Experimental Procedures Committee, Ottawa General Hospital, Ottawa, Ontario, Canada. Written informed consent was obtained from 12 healthy volunteers (six men and six women). The mean (± standard deviation) age and weight of the subjects were 35 ± 8 years and 70 ± 11 kg, respectively. Volunteers were excluded on the basis of the following: pregnancy, hypersensitivity reactions to any drug, use of any medications, chronic illness, current infection, abnormal finding on physical examination, abnormal renal or hepatic function tests, and abnormal hematology or urinalysis. On the morning of each study day, subjects were admitted to the Clinical Investigation Unit, Ottawa General Hospital.The study design was a randomized, two-period, two-treat- ment, two-sequence crossover with a 7-day washout period. Subjects were instructed to fast overnight and were not allowed to eat until 4 h after administration of the study medications. In on...

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Computational study of fluoroquinolone binding to Mg(H2O)N2+ and its applicability to future drug design

Bridle¹,

Janesko²

2017

Int J Quantum Chem

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Fluoroquinolones are an important therapeutic class in the targeting of new and resistant bacterial infections. Fluoroquinolones bind to bacterial type II topoisomerase via a water-Mg 21 bridge.However, binding to magnesium-containing molecules outside of the target cells increases the minimum inhibitory concentration (MIC) and promotes drug resistance. As a result, fluoroquinolones are counter-indicated with magnesium and multivalent metal cation containing drugs, such as antacids. The antibiotic efficacy of fluoroquinolones has also been shown to be pH dependent, as we show the effect of protonation state on magnesium binding. This work presents a systematic computational study of fluoroquinolones' magnesium-binding properties. We use B3LYP density functional theory and triple-zeta basis sets, to evaluate Mg H 2 O ð Þ 21 N binding affinities. Complexation is predicted to be thermodynamically favorable at neutral and basic compared to acidic pH. The calculated complexation energies broadly capture experimental binding affinities, suggesting this is a valid approach for designing new fluoroquinolones with a target magnesium binding affinity. We also investigate the effect of chemical substitution at the carboxylic acid to help in the identification of potential new antibiotics based on the fluoroquinolone pharmacophore. K E Y W O R D S binding affinity, computational, fluoroquinolones, metal complexes 1 | I N T R O D U C T I O N Fluoroquinolones are a class of broad spectrum antibiotic drugs based on the general quinolone pharmacophore, fluorinated at carbon R 6 (Figure 1). FIG URE 1 Essential fluoroquinolone structure Int J Quantum Chem. 2017;117:e25428.

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Norfloxacin interaction with antacids and minerals.

Cited by 51 publications

References 6 publications

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Effect of bismuth subsalicylate on ciprofloxacin bioavailability

Computational study of fluoroquinolone binding to Mg(H2O)N2+ and its applicability to future drug design

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