Protonation equilibrium and lipophilicity of moxifloxacin

Langlois, Michel; Montagut, Martine; Dubost, Jean‐Pierre; Grellet, Jean; Saux, Marie-Claude

doi:10.1016/j.jpba.2004.10.022

Cited by 95 publications

(48 citation statements)

References 16 publications

(17 reference statements)

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“…As a consequence, at the highest concentrations (over 350 g/ml), active transport is saturated and the P app is due essentially to passive permeability (P app Min ϭ 7.9 ϫ 10 Ϫ6 cm ⅐ s Ϫ1 ). This relatively high passive permeability is consistent with the MXF apparent log P of Ϫ0.28, which is characteristic of a lipophilic compound (13). On the other hand, the P app Max obtained for the lowest concentrations (below 10 g/ml) was 13.6 ϫ 10 Ϫ6 cm ⅐ s Ϫ1 , representing the active plus passive transport of MXF.…”

Section: Discussionsupporting

confidence: 79%

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model

Brillault

Castro

Harnois

et al. 2009

Antimicrob Agents Chemother

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Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent P max ‫؍‬ 13.6 ؋ 10 ؊6 cm ⅐ s ؊1 ; apparent K m ‫؍‬ 147 M), suggesting saturated transport at concentrations higher than 350 g/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This Pglycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators.Fluoroquinolones (FQs) are one of the main classes of antimicrobial agents, with a broad spectrum of activity and a concentration-dependent killing effect (25,29). Moxifloxacin (MXF) is an FQ that has been shown to be effective against respiratory pathogens, including Haemophilus influenzae, Moraxella catarrhalis, and penicillin-resistant strains of Streptococcus pneumoniae (3,24). The use of MXF is recommended as therapy for patients with community-acquired pneumonia, exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, or tuberculosis (21). Pharmacokinetics of FQs have been studied in different tissues, such as the liver, kidney, and intestinal tract, and it appears that multiple transporters contribute to drug disposition (2). Active transport has been suggested for many FQs, involving mainly the ATP-binding cassette (ABC) transporter family (P-glycoprotein [P-gp] and multidrug resistance-related proteins [MRPs]). However, there is a lack of information regarding the mechanisms of MXF lung distribution. To our knowledge, cellular transport of MXF through the lung tissue is still unclear, and an understanding of its mechanisms would help to better predict its pulmonary disposition, which is directly linked to the bacterial killing effect. Moreover, when MXF is used as a second-line therapy or in combination with drugs such as rifampin (22), drug-drug interaction can occur, as presented in some rifampin-MXF interaction studies (23,30). In this particular case, MXF was recommended for the treatment of multidrugresistant tuberculosis and a decrease in MXF plasma concentration was observed in assoc...

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Section: Discussionsupporting

confidence: 79%

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model

Brillault

Castro

Harnois

et al. 2009

Antimicrob Agents Chemother

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“…The good abscess penetration of moxifloxacin apparently occurs due to its lipophilicity [10]. Moxifloxacin has been reported to accumulate in different tissues or epithelial lining fluid [11,12].…”

Section: Resultsmentioning

confidence: 99%

Good Penetration of Moxifloxacin into Human Abscesses

Sauermann

Karch²,

Kjellsson³

et al. 2012

Pharmacology

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Abscesses are often treated with antibiotics in addition to incision or when incision is unfeasible, but accurate information about antibiotic abscess penetration in humans is missing. This study aimed at evaluating the penetration of moxifloxacin into human abscesses. After administration of a single dose of 400 mg moxifloxacin, drug concentrations were measured in 10 differently located abscesses at incision, and in plasma over 8 h. At incision performed 0.9–4.8 h after administration, moxifloxacin concentrations in abscesses ranged from ≤0.01 to 9.2 mg/l (1.9 ± 3.4 mg/l), indicating pronounced drug accumulation in some abscesses. The degree of abscess penetration could not be explained by covariates like the ratio of surface area to volume or pH of abscesses, or by moxifloxacin plasma concentrations. Concluding, moxifloxacin was detectable in most abscesses and may be a useful antibiotic for this indication. However, antibiotic abscess penetration was highly variable and unpredictable, suggesting surgical abscess incision whenever possible.

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“…UV/pH titration was used for determination of microconstants in several cases (e.g. repaglinide [63], moxifloxacin [64]) when the shift in the UV spectrum is due to the ionization of a given functional group.…”

Section: Uv/ph Titrationmentioning

confidence: 99%

Physicochemical Profiling in Drug Research and Development

Takács‐Novák¹

2012

Physico-Chemical Methods in Drug Discovery and Development

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Protonation equilibrium and lipophilicity of moxifloxacin

Cited by 95 publications

References 16 publications

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model

P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model

Good Penetration of Moxifloxacin into Human Abscesses

Physicochemical Profiling in Drug Research and Development

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