The pharmacokinetics of antofloxacin in renally impaired rats

Pang, Xiaoyan; Liu, L; Zhang, D M; Wang, G J; Xie, Lin; Liu, X D

doi:10.1211/jpp.60.5.0014

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…AX is primarily metabolized by CYP3A into pharmacologically inactive demethylated, hydroxylated and N‐oxide derivatives, such as other known fluroquilonones [17,18]. Its average serum elimination half‐life was 20.3–20.6 hr, but this interval might be prolonged in patients with renal insufficiency [19]. C max of AX after single oral dose of 300, 400 and 500 mg administration were 2.91, 3.53, 4.32 mg/ml [8], equivalent to 7.05, 8.55, 10.47 μM, respectively, yielding the ratio of 65.3, 53.85, 43.97 between IC 50 observed for HERG blockade and maximal effective plasma concentration under normal conditions.…”

Section: Discussionmentioning

confidence: 99%

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

Guo¹,

Han

Liu³

et al. 2010

Basic Clin Pharma Tox

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The administration of certain fluoroquinolone antibacterials has recently been linked to QT interval prolongation, raising the clinical concerns over the cardiotoxicity of these agents. In this study, the effects of a novel fluoroquinolone, antofloxacin hydrochloride (AX) on human-ether-à-go-go-related gene (HERG) encoding potassium channels and the biophysical mechanisms of drug action were performed with whole-cell patch-clamp technique in transiently transfected HEK293 cells. The administration of AX caused voltage-and time-dependent inhibition of HERG K + current (I HERG ⁄ MiRP1 ) in a concentration-dependent manner but did not markedly modify the properties of channel kinetics, including activation, inactivation, deactivation and recovery from inactivation as well. In comparison with sparfloxacin (SPX), levofloxacin lactate (LVFX), the potency of AX to inhibit HERG tail currents was the least one, with an IC 50 value of 460.37 lM. By contrast, SPX was the most potent compound, displaying an IC 50 value of 2.69 lM whereas LVFX showed modest potency, with an IC 50 value of 43.86 lM, respectively. Taken together, our data suggest that AX only causes a minor reduction of I HERG ⁄ MiRP1 at the estimated free plasma level.The human-ether-à-go-go-related gene (HERG) encodes the pore-forming a-unit of the K + channel that resembles the rapid component of the delayed rectifier current I Kr in cardiac myocytes and non-cardiac cells [1]. It is well established that the inhibition of cardiac I Kr is associated with druginduced QT prolongation torsades de pointes arrhythmias (TdP) and sudden cardiac death. Indeed, it is now known that structurally diverse drugs associated with LQT syndromes (LQTS), including class III anti-arrhythmics, antimicrobials, prokinetic drugs, antihistamines, antidepressants and antipsychotic agents as well, share a common ability of blockage on HERG K + channels, resulting in a delay of cardiac repolarisation [2]. The fluoroquinolone class of antibacterials is widely prescribed for the treatment of infections due to their broad-spectrum antibiotic activity. However, the administrations of certain fluoroquinolone antibacterials have recently been linked to QT interval prolongation, raising the clinical concerns over the cardiotoxicity of these agents. For instance, sparfloxacin (SPX) and grepafloxacin (GPX) have been shown to prolong QT interval on electrocardiogram (ECG) at clinical doses [3][4][5]. In addition, they can induce TdP, a life-threatening ventricular arrhythmia [6,7], resulting in their withdrawn from the market in most countries. Antofloxacin hydrochloride (AX) is a newly developed fluoroquinolone antibiotic in China ( fig. 1). Compared with other available fluoroquinolones in clinical use, AX was well tolerated and demonstrated rapid absorption, highserum concentration, broad tissue distribution, and a long elimination half-life in both animal and human beings from a pharmacokinetic point of view [8,9]. This study aimed to examine the effects of AX on HERG currents het...

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Section: Discussionmentioning

confidence: 99%

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

Guo¹,

Han

Liu³

et al. 2010

Basic Clin Pharma Tox

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“…Antofloxacin hydrochloride is the latest developed 8‐amino derivative of levofloxacin that has high antibacterial activity{( S )‐9‐fluoro‐2,3‐dihydro‐3‐methyl‐8‐amino‐10‐(4‐methyl‐1‐piperazinyl)‐7‐oxo‐7H‐pyrido‐[1.2.3‐ dl ] [1.4] benzoxazine‐6‐carboxylic acid hydrochloride; Pang et al, }. It was first developed by Huan‐Qiu Pharmaceutical Company (Bengbu, Anhui Province, China), and its chemical structure is shown in Figure .…”

Section: Introductionmentioning

confidence: 99%

Simultaneous quantification of antofloxacin and its major metabolite in human urine by HPLC–MS/MS, and its application to a pharmacokinetic study

Zhang

Xie

et al. 2017

Biomedical Chromatography

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This study presents a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous determination of antofloxacinin and its main metabolite - N-demethylated metabolite (N-DM) - in human urine. Ornidazole was used as the internal standard. This was a clinical urine recovery study, in which 10 healthy Chinese volunteers were intravenously administered a single 200 mg dose of antofloxacin hydrochloride. Compounds were extracted by albumen precipitation, after which samples were isocratically eluted using a Poroshell 120 SB-C column, and were analysed using HPLC-MS/MS under electronic spray ionization positive ion mode. The method was successfully applied in a urine pharmacokinetic study of antofloxacinin, with a detection range of 0.02/0.01 to 200/100 μg/mL (for antofioxacin/N-DM).The average percentages of antofioxacin/N-DM measured in urinary excretion frp, 10 volunteers were 54.9 ± 5.7/8.2 ± 2.5% in 120 h duration.

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“…Antofloxacin, a newly developed active quinolone carboxylic acid derivate, exhibits effective antibacterial activity through inhibiting aerobic and anaerobic Gram-positive and Gram-negative bacteria [2]. We had previously developed and validated a quantitative method for the determination of antofloxicin in plasma [3].…”

Section: Introductionmentioning

confidence: 99%

Application of a hybrid ion trap/time-of-flight mass spectrometer in metabolite characterization studies: Structural identification of the metabolism profile of antofloxacin in rats rapidly using MSn information and accurate mass measurements

Liang

Liu

et al. 2009

Journal of Pharmaceutical and Biomedical Analysis

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The pharmacokinetics of antofloxacin in renally impaired rats

Cited by 5 publications

References 15 publications

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

Simultaneous quantification of antofloxacin and its major metabolite in human urine by HPLC–MS/MS, and its application to a pharmacokinetic study

Application of a hybrid ion trap/time-of-flight mass spectrometer in metabolite characterization studies: Structural identification of the metabolism profile of antofloxacin in rats rapidly using MSn information and accurate mass measurements

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