Pharmacokinetics of danofloxacin after single oral and intravenous administration in non-laying hens.

The current study aimed to explore the pharmacokinetics of danofloxacin in non-laying hens after a single oral (PO) and intravenous (IV) dose, both at 5 mg/kg body weight (BW). Eighteen 13-week-old healthy hens were equally and randomly divided into two groups. After both doses, blood samples (approximately 1 ml) were collected at different time points. Danofloxacin concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method followed by a non-compartmental analysis using the software of WinNonLin. The elimination half-lives (t1/2λz s) after PO and IV routes were determined as 8.15 ± 3.37 and 7.69 ± 3.40 h, respectively. After IV administration, danofloxacin had an initial concentration (C0 ) of 3.62 µg/ml, a volume of distribution at steady state (VSS ) of 3579.72 ± 454.29 ml/kg, and a total body clearance (Cl) of 0.49 ml/h/g. After PO administration, the absolute bioavailability and absorption half-life (t1/2ka ) were calculated as 100.99% ± 23.10% and 0.82 ± 0.58 h, respectively. Based on the calculated ratio values of AUC/MIC and Cmax /MIC, an oral dose of 5 mg/kg danofloxacin would be expected to successfully treat hens infected with strains with MIC values ≤0.1 µg/ml.

Danofloxacin pharmacokinetics and tissue residues in Bilgorajska geese.

Danofloxacin is a fluoroquinolone developed for veterinary medicine and used in avian species for the treatment of numerous bacterial infections. However, no pharmacokinetic data have been reported in geese. The aim of the study was three-fold: (i) to evaluate the pharmacokinetics of danofloxacin in geese after single oral (PO) and intravenous (IV) administrations; (ii) to define its residue depletion profile in different goose tissues, and (iii) to recreate a multiple-dose simulation in the practical context of large-scale breeding. Twenty-four healthy geese were randomly divided in three groups each composed of eight animals. Group 1 received danofloxacin IV (5 mg/kg) and groups 2 and 3 were treated PO with the same dose. Blood was collected until 24 h (IV; group 1) and 48 h (PO; group 2) after administration. Two animals from group 3 were sacrificed at 6, 10, 24 and 48 h to collect samples of muscle, heart, kidney, liver, and lung. Danofloxacin was quantified in each matrix using a validated high-performance liquid chromatography method with spectrofluorimetric detection and the pharmacokinetic analysis was performed using non-compartmental and compartmental approaches. Danofloxacin showed a moderate elimination half-life (6.61 h), a slow clearance (0.35 mL/g*h) and a large volume of distribution (1.46 mL/g). The peak plasma concentration after PO administration and the time to reach it were 0.96 µg/mL and 1.70 h, respectively. The oral bioavailability was moderate (58%). Higher residue concentration was found in liver and kidney, compared to the other tissues. If the AUC(0-24) value found in the present study is included in the pharmacokinetic/pharmacodynamic index (AUC(0-24)/MIC) for the prediction of fluoroquinolones' efficacy, danofloxacin seems to be effective in geese against gram-negative bacteria with a minimum inhibitory concentration (MIC) < 0.076 µg/mL and against S. pneumoniae with a MIC < 0.29 µg/mL after a single PO dose of 5 mg/kg. Liver and kidney showed the highest drug tissue penetration value, with an explorative withdrawal time of 2.6 and 3.8 days, respectively. A practical multiple-dose regimen simulation does not lead to significant plasma drug accumulation.

Effect of supportive therapy on the pharmacokinetics of intravenous marbofloxacin in endotoxemic sheep.

The purpose of this study was to determine the influences of supportive therapy (ST) on the pharmacokinetics (PK) of marbofloxacin in lipopolysaccharide (LPS)-induced endotoxemic sheep. Furthermore, minimum inhibitory concentration (MIC) of marbofloxacin against Escherichia coli, Mannheimia haemolytica, Pasteurella multocida, Klebsiella pneumoniae, Salmonella spp., and Staphylococcus aureus was determined. The study was performed using a three-period cross PK design following a 15-day washout period. In the first period, marbofloxacin (10 mg/kg) was administered by an intravenous (IV) injection. In the second and third periods, marbofloxacin was co-administered with ST (lactated ringer + 5% dextrose + 0.45% sodium chloride, IV, 20 ml/kg, dexamethasone 0.5 mg/kg, SC) and ST + LPS (E. coli O55:B5, 10 µg/kg), respectively. Plasma marbofloxacin concentration was measured using HPLC-UV. Following IV administration of marbofloxacin alone, the t 1 / 2 λ z , AUC0-∞ , ClT , and Vdss were 2.87 hr, 34.73 hr × µg/ml, 0.29 L hr-1  kg-1 , and 0.87 L/kg, respectively. While no change was found in the MBX + ST group in terms of the PK parameters of marbofloxacin, it was determined that the ClT of marbofloxacin decreased, AUC0-∞ increased, and t 1 / 2 λ z and MRT prolonged in the MBX + ST + LPS group. MIC values of marbofloxacin were 0.031 to >16 µg/ml for E. coli, 0.016 to >16 µg/ml for M. haemolytica, 0.016-1 µg/ml for P. multocida, 0.016-0.25 µg/ml for K. pneumoniae, 0.031-0.063 µg/ml for Salmonella spp., and 0.031-1 µg/ml for S. aureus. The study results show the necessity to make a dose adjustment of marbofloxacin following concomitant administration of ST in endotoxemic sheep. Also, the PK and pharmacodynamic effect of marbofloxacin needs to be determined in naturally infected septicemic sheep following concomitant administration of single and ST.

Pharmacokinetics of injectable marbofloxacin after intravenous and intramuscular administration in red-eared sliders (Trachemys scripta elegans).

Fluoroquinolone antibacterial drugs are currently used in reptilian medicine because of their broad spectrum of activity including the most frequent pathogens of these species. The disposition kinetics of marbofloxacin (MBX) at a single dose of 2 mg/kg were determined in healthy red-eared sliders after intravenous (IV) and intramuscular (IM) administration. The influence of renal portal system on the bioavailability of the drug was investigated by using forelimb and hindlimb as IM injection sites. Apparent volume of distribution at steady-state (Vss ) and systemic clearance (Cl) of marbofloxacin after IV administration were estimated to be 48.21 ± 5.42 ml/kg and 23.38 ± 2.90 ml/hr·kg, respectively. The absolute bioavailabilities after IM route were 45.96% (forelimb) and 52.09% (hindlimb). The lack of statistically significant differences in most of the pharmacokinetic parameters after the two IM injection sites suggests a negligible influence of renal portal system in clinical use of MBX, although the Cmax after IMfore administration is advantageous, having into account the concentration-dependent action of this antibiotic. The absence of visible adverse reactions in the animals and the advantageous pharmacokinetic properties suggest the possibility of its safe and effective clinical use in red-eared sliders.

Population Pharmacokinetics of Danofloxacin After Single Intramuscular Dose Administration in California Brown Pelicans (Pelecanus occidentalis californicus).

The pharmacokinetics of danofloxacin was investigated in rehabilitated California brown pelicans (Pelecanus occidentalis californicus) after a single intramuscular injection at a dose of 15 mg/kg body weight. The concentration of the drug in plasma was assayed by high-pressure liquid chromatography. A sparse-sampling design was used to reduce the number of samples (1-4 venipunctures) obtained from 24 brown pelicans. A population pharmacokinetic analysis with nonlinear mixed-effects modeling was used to accommodate the sparse-sampling strategy. The nonlinear mixed-effects modeling approach measured both fixed effects (typical values for the population) and random effects (between-subject variability) for this population. A 1-compartment model best represented the concentration-versus-time data after injection. After injection, the elimination half-life, peak concentration, area under the curve, and volume of distribution were 2.76 hours, 2.5 µg/mL, 13.75 µg/h/mL, and 4.35 L/kg, respectively. Rate of absorption was highly variable among the birds. The intramuscular injection of danofloxacin in pelicans at this dose produced plasma concentrations that meet therapeutic targets for bacteria with a minimum inhibitory concentration of ≤0.25 µg/mL. This dose can be used for future studies to evaluate the efficacy of danofloxacin for treating susceptible bacteria.

Intracellular Pharmacodynamic Modeling Is Predictive of the Clinical Activity of Fluoroquinolones against Tuberculosis.

Clinical studies of new antitubercular drugs are costly and time-consuming. Owing to the extensive tuberculosis (TB) treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of preclinical models in predicting the activity of fluoroquinolones underline the importance of developing new and more robust predictive tools that will optimize the design of future trials. Here, we used high-content imaging screening and pharmacodynamic intracellular (PDi) modeling to identify and prioritize fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modeling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilization) rates compared to eight independent clinical trials. In addition, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict the relapse rate. These data further support that PDi-based modeling offers a much-needed decision-making tool for the TB drug development pipeline.

High-resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types.

Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology.

Pharmacokinetic evaluation of marbofloxacin after intravenous administration at different ages in llama crias, and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation.

In llama crias (tekes), Escherichia coli and Staphylococcus aureus are major pathogens, and marbofloxacin could be a suitable choice. The objectives of this study were (a) to evaluate the serum pharmacokinetics of marbofloxacin (5 mg/kg) after intravenous administration in tekes and simulate a multidose regimen; (b) to emulate pharmacokinetic profiles after single dose and steady-state conditions by Monte Carlo simulation (c) to determine the MIC of regional strains of Escherichia coli and Staphylococcus aureus; (d) to perform a PK/PD analysis by Monte Carlo simulation. Pharmacokinetics of marbofloxacin was evaluated in six animals at 3, 10, 24, 50, and 80 days after birth. Marbofloxacin were determined by HPLC. A steady-state multi-dose simulation was carried out, and concentration-time profiles were generated by Monte Carlo simulation. MIC of marbofloxacin against regional E. coli and S. aureus strains were also determined. Finally, a PK/PD analysis was conducted by Monte Carlo simulation. After pharmacokinetic analysis, clearance showed a trend to increase (0.14 and 0.18 L kg-1  hr-1 ), and AUC (36.74 and 15.21 µg hr-1  ml-1 ) and Vss (3.06 and 3.37 L/kg) trended to decrease at 3 and 80 days-old, respectively, showing accumulation ~50% in animals with 3 days. All strains tested of E. coli (MIC90  = 0.06 µg/ml) and S. aureus (MIC90  = 0.25 µg/ml) were susceptible to marbofloxacin. PK/PD analysis suggests that the therapeutic regimen of marbofloxacin could be effective for infections caused by E. coli strains in animals between 3 and 80 days, with a CFR for Cmax /MIC > 10 of 100% and for AUC24 /MIC > 125 of 99.99%; and for infections produced by S. aureus in animals between 3 and 24 days old, with a CFR for Cmax /MIC > 10 of 93.08% and for AUC24 /MIC > 60 of 97.01%, but a higher dose should be used in older animals, because PK/PD endpoints were not met.

Individualising Therapy to Minimize Bacterial Multidrug Resistance.

The scourge of antibiotic resistance threatens modern healthcare delivery. A contributing factor to this significant issue may be antibiotic dosing, whereby standard antibiotic regimens are unable to suppress the emergence of antibiotic resistance. This article aims to review the role of pharmacokinetic and pharmacodynamic (PK/PD) measures for optimising antibiotic therapy to minimise resistance emergence. It also seeks to describe the utility of combination antibiotic therapy for suppression of resistance and summarise the role of biomarkers in individualising antibiotic therapy. Scientific journals indexed in PubMed and Web of Science were searched to identify relevant articles and summarise existing evidence. Studies suggest that optimising antibiotic dosing to attain defined PK/PD ratios may limit the emergence of resistance. A maximum aminoglycoside concentration to minimum inhibitory concentration (MIC) ratio of > 20, a fluoroquinolone area under the concentration-time curve to MIC ratio of > 285 and a ß-lactam trough concentration of > 6 × MIC are likely required for resistance suppression. In vitro studies demonstrate a clear advantage for some antibiotic combinations. However, clinical evidence is limited, suggesting that the use of combination regimens should be assessed on an individual patient basis. Biomarkers, such as procalcitonin, may help to individualise and reduce the duration of antibiotic treatment, which may minimise antibiotic resistance emergence during therapy. Future studies should translate laboratory-based studies into clinical trials and validate the appropriate clinical PK/PD predictors required for resistance suppression in vivo. Other adjunct strategies, such as biomarker-guided therapy or the use of antibiotic combinations require further investigation.

Pharmacokinetics of Intravenous Delafloxacin in Patients With End-Stage Renal Disease.

This was an open-label, parallel-group, crossover study that examined the pharmacokinetics and safety of delafloxacin, an anionic fluoroquinolone, after a single intravenous infusion in subjects with end-stage renal disease (ESRD; creatinine clearance <15 mL/min) undergoing hemodialysis compared with healthy subjects. Subjects received 300 mg delafloxacin containing sulfobutylether-ß-cyclodextrin in 2 periods separated by ≥14-day washouts. Blood and urine samples were collected, and pharmacokinetic parameters were calculated using noncompartmental methods. The mean total exposure (area under the curve) of delafloxacin was about 2.1 and 2.6 higher for subjects with ESRD compared to healthy subjects when dosed 1 hour before or 1 hour after hemodialysis, respectively. Compared to subjects with normal renal function, the maximum exposure to delafloxacin was 13% and 33% higher for ESRD subjects given delafloxacin 1 hour before and 1 hour after hemodialysis, respectively. The mean clearance was 13.7 L/h for healthy subjects and was lower for subjects with ESRD when given before (7.39 L/h) or after (5.69 L/h) hemodialysis. The clearance of delafloxacin in dialysate was 4.74 L/h with about 19.2% of the delafloxacin dose recovered after a 4-hour dialysis session. Delafloxacin was well tolerated in both healthy and ESRD subjects, with diarrhea being the most reported treatment-emergent adverse event.

Pharmacokinetics of enrofloxacin and ciprofloxacin in Atlantic horseshoe crabs (Limulus polyphemus) after single injection.

The pharmacokinetics of enrofloxacin and the metabolite ciprofloxacin were studied in horseshoe crabs after a single injection of 5 mg/kg. Twelve Atlantic horseshoe crabs (Limulus polyphemus) of undetermined age were injected with enrofloxacin into the dorsal cardiac sinus. Hemolymph samples were collected by syringe and needle at regular intervals for 120 hr. Samples were analyzed by high-pressure liquid chromatography and compartmental analysis performed on the results. Following injection, the elimination half-life (T½), peak concentration, area under the curve (AUC), and volume of distribution (VD) for enrofloxacin were 27.9 (29.13) hr, 8.98 (18.09) µg/ml, 367.38 (35.41) hr µg/ml, and 0.575 (20.48) L/kg, respectively (mean value, CV%). For ciprofloxacin, the elimination T½, peak concentration, and AUC were 61.36 (34.55) hr, 2.34 (24.11) µg/ml, and 304.46 (24.69) µg hr/ml. In these animals, the ciprofloxacin concentrations comprised an average of 45.8% of the total fluoroquinolone concentrations, which is substantial compared to other marine invertebrates. The total AUC produced (sum of enrofloxacin and ciprofloxacin) was 682.69 ± 180.61 µg hr/ml. Concentrations that were achieved after a single dose of 5 mg/kg horseshoe crabs were sufficient to treat bacteria susceptible to enrofloxacin and ciprofloxacin.

Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.

Comparing efficacies of moxifloxacin, levofloxacin and gatifloxacin in tuberculosis granulomas using a multi-scale systems pharmacology approach.

Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim. GranSim is a hybrid agent-based computational model that simulates granuloma formation and function, FQ plasma and tissue pharmacokinetics and pharmacodynamics and is based on extensive in vitro and in vivo data. We treat in silico granulomas with recommended daily doses of each FQ and compare efficacy by multiple metrics: bacterial load, sterilization rates, early bactericidal activity and efficacy under non-compliance and treatment interruption. GranSim reproduces in vivo plasma pharmacokinetics, spatial and temporal tissue pharmacokinetics and in vitro pharmacodynamics of these FQs. We predict that MXF kills intracellular bacteria more quickly than LVX and GFX due in part to a higher cellular accumulation ratio. We also show that all three FQs struggle to sterilize non-replicating bacteria residing in caseum. This is due to modest drug concentrations inside caseum and high inhibitory concentrations for this bacterial subpopulation. MXF and LVX have higher granuloma sterilization rates compared to GFX; and MXF performs better in a simulated non-compliance or treatment interruption scenario. We conclude that MXF has a small but potentially clinically significant advantage over LVX, as well as LVX over GFX. We illustrate how a systems pharmacology approach combining experimental and computational methods can guide antibiotic selection for TB.

Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review.

BACKGROUND: In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the pharmacokinetics (PK) of antibiotics in this population. The aim of this systematic review was to summarize antibiotic PK data of SSA adult patient populations to clarify whether inappropriate drug concentrations that may also lead to antimicrobial resistance are likely to occur. METHODS: An electronic search was conducted in Ovid MEDLINE, Embase, and the African Index Medicus collecting studies from 1946 to May 2016. Reviewers independently selected studies reporting outcome data on volume of distribution (V), clearance, and half-life. Relevant information was abstracted and quality assessed. RESULTS: Twelve studies were selected, addressing 6 antibiotic classes. There were 6 studies on fluoroquinolones and 1 on ß-lactam antibiotics. Nine out of 12 originated from South Africa and 6 of those dealt with intensive care unit (ICU) populations. The quality of most studies was low. Studies on amikacin, teicoplanin, and ertapenem (n = 4) displayed a pattern of a large V with low drug concentrations. Fluoroquinolone PK changes were less prominent and more diverse whereas the probability of pharmacodynamic target attainment was low for the treatment of tuberculosis in South Africa. Interindividual variability of V was high for 10/12 studies. CONCLUSIONS: Antibiotic PK data of SSA adult patient populations are scarce, but disease-induced inappropriate drug concentrations do occur. Data from non-ICU, severely ill patients, and ß-lactam data are particularly lacking, whereas ß-lactam antibiotics are commonly used, and typically vulnerable to disease-induced PK changes. Studies investigating the PK and pharmacodynamics of ß-lactam antibiotics in severely ill, adult SSA patient populations are needed to improve local antibiotic dosing strategies.

Penetration of 0.3% ciprofloxacin, 0.3% ofloxacin, and 0.5% moxifloxacin into the cornea and aqueous humor of enucleated human eyes.

We aimed to quantify the penetration of ciprofloxacin, ofloxacin, and moxifloxacin into the cornea and aqueous humor of cadaver eyes. A total of 60 enucleated eyes, not eligible for corneal transplantation, were divided into three groups and immersed in commercial solutions of 0.3% ciprofloxacin, 0.3% ofloxacin, or 0.5% moxifloxacin for 10 min. Whole corneas and samples of aqueous humor were then harvested and frozen, and drug concentrations analyzed by liquid chromatography tandem mass spectrometry. The mean corneal concentration of moxifloxacin was twice as high as ofloxacin, and the latter was twice as high as ciprofloxacin. The mean concentration of moxifloxacin in the aqueous humor was four times higher than the other antibiotics, and the mean concentrations of ciprofloxacin and ofloxacin were statistically similar. The amount of drug that penetrated the anterior chamber after a 10-min immersion was far below the safe limit of endothelial toxicity of each preparation. Moxifloxacin demonstrated far superior penetration into the cornea and anterior chamber of cadaver eyes compared to ciprofloxacin and ofloxacin. One should not expect endothelial toxicity with the commercial eye drops of ciprofloxacin, ofloxacin, and moxifloxacin that reach the anterior chamber through the cornea.

Sensitivity and Reliability of Halothane-anaesthetized Microminipigs to Assess Risk of Drug-induced Long QT Syndrome.

Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 µg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane-anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.

Impact of Fusarium mycotoxins on hepatic and intestinal mRNA expression of cytochrome P450 enzymes and drug transporters, and on the pharmacokinetics of oral enrofloxacin in broiler chickens.

Cytochrome P450 (CYP450) drug biotransformation enzymes and multidrug resistance (MDR) proteins may influence drug disposition processes. The first part of the study aimed to evaluate the effect of mycotoxins deoxynivalenol (DON) and/or fumonisins (FBs), at contamination levels approaching European Union guidance levels, on intestinal and hepatic CYP450 enzymes and MDR proteins gene expression in broiler chickens. mRNA expression of genes encoding CYP450 enzymes (CYP3A37, CYP1A4 and CYP1A5) and drug transporters (MDR1/ABCB1 and MRP2/ABCC2) was determined using qRT-PCR. A significant up-regulation of CYP1A4 (P = 0.037) and MDR1 (P = 0.036) was observed in the jejunum of chickens fed a diet contaminated with FBs. The second part of this study aimed to investigate the impact of feeding a FBs contaminated diet on the oral absorption of enrofloxacin (10 mg/kg BW), a MDR1 substrate. A significant (P = 0.045), however small, decreased area under the plasma concentration-time curve (AUC0-48 h, mean ± SD) was observed for enrofloxacin in chickens fed the FBs contaminated diet compared to the control group, 16.28 ± 1.82 h µg/mL versus 18.27 ± 1.79 h µg/mL. These findings suggest that concurrent administration of drugs with FBs contaminated feed might alter the pharmacokinetic characteristics of CYP1A4 substrate drugs and MDR1 substrates, such as enrofloxacin.

Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue.

OBJECTIVES: This study aimed to investigate the penetration of fluoroquinolones into human epididymal tissue. METHODS: The penetration of levofloxacin (LVFX) 500 mg or sitafloxacin (STFX) 100 mg into epididymal tissue was examined. Patients with prostate cancer who were referred for orchiectomy were included. LVFX 500 mg (n = 9) or STFX 100 mg (n = 9) was administered orally 1 h before orchiectomy, and 0.5 g of epididymal tissue and blood samples were collected simultaneously during surgery. Drug concentrations were measured by high-performance liquid chromatography, and patient characteristics and adverse events were analyzed. RESULTS: The mean ratio of the epididymal concentration to the serum concentration was 1.48 ± 0.45 for LVFX and 1.54 ± 0.81 for STFX. For LVFX, the simulated curves estimated the following: maximum concentrations (Cmax) of 8.84 µg/ml in serum and 14.1 µg/g in epididymal tissue and area under the concentration-time curve for 24 h (AUC24) of 68.5 µg h/ml in serum and 108.9 µg h/g in epididymal tissue. For STFX, the Cmax was 1.22 µg/ml in serum and 1.66 µg/g in epididymal tissue, and the AUC24 was 9.58 µg h/ml in serum and 13.1 µg h/g in epididymal tissue. Neither treatment-related adverse events nor postoperative urogenital infections were observed. CONCLUSIONS: The results of this study suggest that oral administration of LVFX 500 mg or STFX 100 mg achieves effective epididymal concentrations for treatment of epididymitis.

Pharmacokinetics of marbofloxacin in freshwater crocodiles (Crocodylus siamensis) after intravenous and intramuscular administration.

To evaluate the fate and disposition of marbofloxacin (MBF) in freshwater crocodiles (Crocodylus siamensis), MBF was administered either intravenously (i.v.) or intramuscularly (i.m.) at a dosage of 2.0 mg/kg body weight. The concentrations of MBF in plasma were measured using high-performance liquid chromatography equipped with a fluorescence detector. The concentrations of MBF in the plasma were measurable up to 144 h after i.v. and i.m. administration. After the first 45 min, the mean pharmacokinetic profiles produced by the two administration routes were almost identical. No statistically significant differences in the pharmacokinetic parameters between the groups were observed. The half-life was long (about 2.5 days), the volume of distribution was large (about 1.44 L/kg), λz was small (0.01 h-1 ), and the clearance was slow (22.6 mL/h/kg). The absolute i.m. bioavailability (F%) was 105.36%. The dose of MBF administered in this study seems to produce appropriate PK-PD parameters that predict antibacterial success for disease caused by susceptible bacteria. More studies are warranted to evaluate the likely residues after administration of multiple doses.

Pharmacokinetics and distribution in interstitial and pulmonary epithelial lining fluid of danofloxacin in ruminant and preruminant calves.

The objective of this study was to compare active drug concentrations in the plasma vs. different effector compartments including interstitial fluid (ISF) and pulmonary epithelial lining fluid (PELF) of healthy preruminating (3-week-old) and ruminating (6-month-old) calves. Eight calves in each age group were given a single subcutaneous (s.c.) dose (8 mg/kg) of danofloxacin. Plasma, ISF, and bronchoalveolar lavage (BAL) fluid were collected over 96 h and analyzed by high-pressure liquid chromatography. PELF concentrations were calculated by a urea dilution assay of the BAL fluids. Plasma protein binding was measured using a microcentrifugation system. For most preruminant and ruminant calves, the concentration-time profile of the central compartment was best described by a two-compartment open body model. For some calves, a third compartment was also observed. The time to maximum concentration in the plasma was longer in preruminating calves (3.1 h) vs. ruminating calves (1.4 h). Clearance (CL/F) was 385.15 and 535.11 mL/h/kg in preruminant and ruminant calves, respectively. Ruminant calves maintained higher ISF/plasma concentration ratios throughout the study period compared to that observed in preruminant calves. Potential reasons for age-related differences in plasma concentration-time profiles and partitioning of the drug to lungs and ISF as a function of age are explored.