Dose ranging pharmacokinetics and brain distribution of norfloxacin using microdialysis in rats

Marchand, Sandrine; Chenel, Marylore; Lamarche, Isabelle; Pariat, Claudine; Couet, William

doi:10.1002/jps.10504

Cited by 17 publications

(27 citation statements)

References 20 publications

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“…One is the presence of active efflux transport systems, which have been proposed as an explanation for the limited muscle tissue distribution of norfloxacin (14). Such systems are found in specific tissues or organs, such as the brain, and are responsible for tissue AUC-to-blood AUC ratios less than unity (3,23); they are also equal to the corresponding influx distribution-to-efflux distribution clearance ratios (3,33). However, there is no evidence to support the presence of such systems in soft tissues, such as muscle tissue.…”

Section: Discussionmentioning

confidence: 99%

“…On the day before the experiment, the rats were anesthetized by isoflurane (Forene, Abbot, Rungis, France) inhalation (23,24). Polyethylene cannulas were inserted into the left femoral vein and artery for drug administration and blood sampling, and two CMA/20 probes (polycarbonate; membrane length, 10 mm; CMA microdialysis; Phymep, Paris, France) were inserted into the right jugular vein and the right hind leg muscle as described previously (24).…”

Section: Methodsmentioning

confidence: 99%

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Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

Marchand

Dahyot

Lamarche

et al. 2005

Antimicrob Agents Chemother

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The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg ؊1 over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n ‫؍‬ 8) and control (n ‫؍‬ 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P < 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.Nosocomial infections are of primary concern in critical care departments; and because hospitalized patients suffer from major physiological alterations with potential consequences on drug pharmacokinetics, selection of the appropriate antibiotic dosing regimens appears to be very challenging (28). Because infections occur in tissues, measurement of free antibiotic concentrations in the interstitial fluid of tissues should be the most relevant for prediction of therapeutic efficacy, at least for extracellular pathogens. Microdialysis is an elegant technique that allows such determinations (6) and that has been used to demonstrate that the tissue distributions of several antibiotics, including piperacillin (2, 15), cefpirome (16), meropenem (32), and imipenem (IPM) (31), were impaired in critical care patients. However, not only the disease state itself but also iatrogenic procedures, such as surgery or intensive care treatment, might influence drug kinetics (2, 17); and therefore, the reasons for the altered distribution are not clear. Yet, it was hypothesized that reduced tissue perfusion contributes to the reduced IPM distribution (31).Experiments with animals allow better control of these multiple interfering parameters, and many microdialysis studies have also been conducted with rats to investigate the distribution of amino ␤-lactams in muscle (4,7,18,20,21,22,24,25). Muscle tissue has frequently been chosen because it is relatively accessible and the concentrations in muscle tissue seem to be a reasonable predictor of the unbound concentrations in more therapeutically relevant tissues, such as lung tissue (7,20,21). A microdialysis study condu...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

Marchand

Dahyot

Lamarche

et al. 2005

Antimicrob Agents Chemother

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“…Ringer solution for blood microdialysis was from CMA (perfusion fluid T1; CMA Microdialysis, Phymep) and Ringer medium for brain microdialysis was as described previously (2,9). After the equilibration period, four dialysates were collected for 60 min by fractions corresponding to 15-min intervals, and the mean in vivo recovery was determined for each probe and used to estimate actual unbound concentrations (9). A 2-h washout period was then performed, with probes being perfused with blank Ringer at a flow rate of 2 l · min Ϫ1 and 0.5 l · min Ϫ1 for the first and second hours, respectively.…”

mentioning

confidence: 99%

“…Samples were collected at 15-and 30-min intervals during the first and second hours, respectively, and then every hour over the remaining 6 h. The NOR assay with dialysates was as described previously (2,9). Drug concentrations in blood and brain extracellular fluid (ECF) were analyzed simultaneously by a population approach.…”

mentioning

confidence: 99%

“…Drug concentrations in blood and brain extracellular fluid (ECF) were analyzed simultaneously by a population approach. Distribution equilibrium of NOR within the brain was supposed to be attained instantaneously (2,9), and blood and brain ECF data were analyzed simultaneously, considering that brain ECF was part of the central compartment, with a tissue penetration factor (R) relating free brain ECF and free blood drug concentrations at any time (2). The population pharmacokinetic (PK) model after i.v.…”

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confidence: 99%

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Norfloxacin Blood-Brain Barrier Transport in Rats Is Not Affected by Probenecid Coadministration

Marchand

Forsell

Chenel

et al. 2006

Antimicrob Agents Chemother

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The effect of probenecid (PRO) on norfloxacin (NOR) blood-brain barrier transport was investigated with rats by microdialysis. Maximum brain drug concentrations were rapidly attained, and the brain penetration factor was close to 5% in the absence and presence of PRO. In conclusion, PRO has no effect on NOR blood-brain barrier transport.Central nervous system (CNS) side effects represent a common adverse event during fluoroquinolone (FQ) therapy (3, 7). High potential toxic risk exists with FQs exhibiting limited CNS distribution, such as norfloxacin (NOR) (2, 5, 6, 9), because of possible blood-brain barrier (BBB) permeation under various conditions, such as disease state or drug-drug interactions. Probenecid (PRO) is known as an inhibitor of anionic transport proteins, such as multidrug resistance-associated protein, organic anion transporting polypeptides, and organic anion transporters (8, 13), previously shown to interfere with the renal tubular secretion of NOR, at least in rabbits and humans (12). PRO could therefore be responsible for drugdrug interactions at the BBB by various mechanisms and was selected as a good candidate drug with potential effect on the CNS distribution of NOR, chosen as a representative FQ with limited CNS distribution.NOR and PRO were obtained from Sigma (Saint-Quentin Fallavier, France). A NOR salt was prepared as described previously (5). Solvents, including water, were of analytical grade. Experiments were done in accordance with the Principles of Laboratory Animals Care (NIH Publication no. #85-23, revised in 1985). Male Sprague-Dawley rats (Janvier Laboratories, Le Genet-St-Isle, France) weighing 287 Ϯ 8 g were anesthetized and equipped with catheters (2, 9) and blood microdialysis CMA/20 probes (polycarbonate; membrane length, 10 mm; cutoff, 20,000 Da; CMA Microdialysis, Phymep, Paris, France) (10,14,17). Anesthetized rats were placed on a stereotaxic instrument (David Kopf Instruments, Tujunga, Calif.) and a CMA/12 guide cannula was implanted into the left dorsal hippocampus (2, 9). The day of the experiment, a CMA/12 probe (polycarbonate; membrane length, 3 mm; cutoff, 20,000 Da; CMA Microdialysis, Phymep) was inserted into the dorsal hippocampus. To estimate individual in vivo recovery, a retrodialysis by drug period was done, consisting of an equilibration and a collection period. Probes were then perfused with Ringer containing NOR (100 nM for brain, 6 M for blood) at 2 l · min Ϫ1 during the first hour of equilibration and 0.5 l · min Ϫ1 during the second hour. Ringer solution for blood microdialysis was from CMA (perfusion fluid T1; CMA Microdialysis, Phymep) and Ringer medium for brain microdialysis was as described previously (2, 9). After the equilibration period, four dialysates were collected for 60 min by fractions corresponding to 15-min intervals, and the mean in vivo recovery was determined for each probe and used to estimate actual unbound concentrations (9). A 2-h washout period was then performed, with probes being perfused with blank Ringer

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On The Rate and Extent of Drug Delivery to the Brain

et al. 2007

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Abstract. To define and differentiate relevant aspects of blood-brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: K p,uu (concentration ratio of unbound drug in brain to blood), CL in (permeability clearance into the brain), and V u,brain (intra-brain distribution). The permeability of the blood-brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. K p,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (K p ), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters K p,uu , CL in , and V u,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes.

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Dose ranging pharmacokinetics and brain distribution of norfloxacin using microdialysis in rats

Cited by 17 publications

References 20 publications

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

Norfloxacin Blood-Brain Barrier Transport in Rats Is Not Affected by Probenecid Coadministration

On The Rate and Extent of Drug Delivery to the Brain

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