Scholarly article on topic 'Some pharmacokinetic aspects and bioavailability of marbofloxacin in foals'

Some pharmacokinetic aspects and bioavailability of marbofloxacin in foals Academic research paper on "Veterinary science"

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Abstract of research paper on Veterinary science, author of scientific article — M.A. Tohamy, A.A.M. El-Gendy

Abstract The single-dose pharmacokinetics of marbofloxacin was studied in clinically normal foals after intravenous and intramuscular administration of 5 mg of marbofloxacin/kg of body weight. Marbofloxacin concentrations were determined by microbiological assay method. The disposition of marbofloxacin was best described by a two-compartment open model after a single intravenous injection while, by a one-compartment open model after intramuscular administration. The distribution half-life, elimination half-life, mean residence time of marbofloxacin after intravenous injection were 0.27, 6.4, 6.8 h after 5 mg/kg dose. Following intramuscular administration, the drug absorbed at a fast rate as indicated by short absorption half-life (t 0.5(ab)) of 0.26 h. The drug was eliminated at a slow rate with an elimination half-life t 0.5(el) of 7.16 h after 5 mg/kg dose. The extent of serum protein binding was 27.5%. These results indicate that a dose of 5 mg of marbofloxacin/kg administered as a single dose once daily could be useful in the treatment of diseases caused by sensitive pathogens in foals after specific assessments.

Academic research paper on topic "Some pharmacokinetic aspects and bioavailability of marbofloxacin in foals"

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Some pharmacokinetic aspects and bioavailability of marbofloxacin in foals

M.A. Tohamy*, A.A.M. El-Gendy

Pharmacology Department, Faculty of Veterinary Medicine, Beni-Suef University, Egypt

ARTICLE INFO

ABSTRACT

Article history: Received 11 August 2012 Accepted 18 December 2012 Available online 13 September 2013

Keywords:

Marbofloxacin

Pharmacokinetics Bioavailability

The single-dose pharmacokinetics of marbofloxacin was studied in clinically normal foals after intravenous and intramuscular administration of 5 mg of marbofloxacin/kg of body weight. Marbofloxacin concentrations were determined by microbiological assay method. The disposition of marbofloxacin was best described by a two-compartment open model after a single intravenous injection while, by a one-compartment open model after intramuscular administration. The distribution half-life, elimination half-life, mean residence time of marbofloxacin after intravenous injection were 0.27, 6.4, 6.8 h after 5 mg/kg dose. Following intramuscular administration, the drug absorbed at a fast rate as indicated by short absorption half-life (t0.5(ab)) of 0.26 h. The drug was eliminated at a slow rate with an elimination half-life t0.5(el) of 7.16 h after 5 mg/kg dose. The extent of serum protein binding was 27.5%. These results indicate that a dose of 5 mg of marbofloxacin/kg administered as a single dose once daily could be useful in the treatment of diseases caused by sensitive pathogens in foals after specific assessments.

Copyright 2013, Beni-Suef University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

Fluoroquinolones are antimicrobial drugs that generally have very good activity against a broad spectrum of aerobic gramnegative including Pasteurella spp., some gram-positive bacteria and against mycoplasma (Hannan et al., 1997). Fluo-roquinolones have other desirable characteristics such as large volumes of distribution, low serum protein binding and relatively low minimum inhibitory concentrations (MIC)

against susceptible target microorganisms (Brown, 1996). Marbofloxacin is a second generation fluoroquinolone (Martinez et al., 2006) approved exclusively for animal clinical use. It has broad spectrum bactericidal activity against Gramnegative bacteria, Gram-positive bacteria and Mycoplasma species (Drugeon et al., 1997; Meunier et al., 2004). It has some pharmacokinetic properties such as a long elimination halflife (t0 5(el)), and high bioavailability after oral administration (Heinen, 2002). The pharmacokinetics of marbofloxacin has

* Corresponding author. Tel./fax: +20 82 2327982.

E-mail address: eaaa_t@yahoo.com (M.A. Tohamy). Peer review under the responsibility of Beni-Suef University

2314-8535/$ — see front matter Copyright 2013, Beni-Suef University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bjbas.2013.09.007

been extensively investigated in adult donkeys (Gonzalez et al., 2007) and horses (Bousquet-Melou et al., 2002; Carretero et al., 2002; Peyrou et al., 2004) but no data are available in foals. Consequently, the purpose of the present study was to investigate the bioavailability and pharmacoki-netics of marbofloxacin in foals following a single intravenous (IV) and intramuscular (IM) administration of 5 mg/kg of body weight.

2. Materials and methods

2.1. Drug

Marbofloxacin was used as a 10% injectable aqueous solution obtained from Veterinary Pharmaceutical Laboratories, France (Marbocyl®, Vetoquinol, Lure, France). Marbofloxacin standard was provided by Vetoquinol (Lure, France).

2.2. Animals

Six clinically healthy male and female Egyptian foals weighing 200-250 kg b. wt. (9-11 months of age) were used. Animals were kept under good hygienic condition and none of them were treated with antibiotics for one month prior to the trial.

2.3. Experimental design

The foals were given a single intravenous (into the right jugular vein) and intramuscular (into the deep gluteal muscle of hindquarters) dose of 5 mg/kg 10% aqueous solution of mar-bofloxacin (Carpenter et al., 2009) with a two weeks washout period between each route. Blood samples were collected from the left jugular vein just before drug administration and at 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h after drug administration. The blood was allowed to clot at room temperature, and then the serum was separated by centrifugation at 3000 g for 15 min. Serum samples were stored at -20 °C until assayed. Three foals showed only slight swelling at the site of injection and diarrhea in one foal.

2.4. Drug assay

Marbofloxacin concentrations in serum samples were determined by the microbiological assay method described by Tsai and Kondo (2001) using Escherichia coli (ATCC 25922) as a test organism. Standard curves were constructed using antibacterial-free serum collected from foals. Six wells, 8 mm in diameter were cut at equal distances in standard petri dishes containing 25 ml seeded agar. The wells were filled with 100 ml of either the test samples or marbofloxacin standards. The plates were incubated at 37 ° C for 24 h. The inhibition zone diameters were measured and the marbofloxacin concentrations in the test samples were calculated from the standard curve. The limit of detection of the marbofloxacin assay was 0.02 ug/ml. Semi-logarithmic plots of the inhibition zone diameter versus standard marbofloxacin concentrations in serum were linear with typical correlation coefficient of 0.97. The extent of protein binding was determined in vitro according to the method described previously by Craig and

Suh (1991) with marbofloxacin concentrations 0.02, 0.04, 0.08, 0.156, 0.313, 0.625, 1.25, 2.5 and 5 ug/ml in serum and phosphate buffered saline (pH 7.2). This method was based on the diffusion of free antibiotic into the agar medium. The differences in the diameters of the inhibition zones between the solutions of the drug in the buffer and serum samples were then calculated according to the following equation:

Protein binding% =(Zone of inhibition in buffer

- Zone of inhibition in serum/Zone of inhibition in buffer) x 100

2.5. Pharmacokinetic analysis

Serum concentrations of marbofloxacin after IV and IM administrations were subjected to a compartmental analysis using a nonlinear least-squares regression analysis. The analysis was done with the help of a computerized curve-stripping software package (R STRIP, Version 5.0; Micromath Scientific Software, Salt Lake City, UT, USA). Data were examined by sequential weighted nonlinear regression. Mono-exponential and bi-exponential equations were fitted to individual serum concentration-time data. Akaike's Information Criterion (Yamaoka et al., 1978), residual sum of squares, and analysis of the residual's plots were used to discriminate between models (Powers, 1990). Following IV injection, the serum concentration-time relationship was best estimated as a two-compartment open model system (Baggot, 1978) according to the following bi-exponential equation: Cp = Ae-at + Be-bt, where Cp is the concentration of drug in the serum at time t; A is the intercept of the distribution phase with the concentration axis expressed as mg/ml-; B is the intercept of the elimination phase with the concentration axis expressed as mg/ml; a is the distribution rate constant expressed in units of reciprocal time (h-1); b is the elimination rate constant expressed in units of reciprocal time (h-1); and e is the natural logarithm base.

After IM administration, data was analyzed by adopting a one-compartment model. This program also calculated non-compartmental parameters using the statistical moment theory (Gibaldi and Perrier, 1982). The Cmax (maximum serum concentration) and tmax (time of maximum serum concentration) were obtained from individual tabulated values (observed values). The terminal elimination half-life (t0.5(el)) and absorption half-life (t0.5(ab)) were calculated as ln2/Kel or ln2/Kab, respectively, where Kel and Kab are the elimination and absorption rate constants, respectively. The area under serum concentration-time curve (AUC) and area under the first moment curve (AUMC) were calculated using the trapezoidal method and extrapolation to infinity (Baggot, 1978). The mean residence time (MRT) was calculated as MRT = AUMC/AUC. The total body clearance (ClB) was calculated as ClB = Dose/AUC and the absolute bioavailability (F) as F = AUCim/AUCiv100 (Gibaldi and Perrier, 1982). The results obtained were expressed as mean and standard error (SE). Standard errors were calculated from the mean data according to Snedecor and Cochran (1976).

2.6. Pharmacodynamic analysis

Several pharmacodynamic (PD) parameters including the maximum serum concentration/minimum inhibitory

Time (hours)

Fig. 1 - Semi-logarithmic graph depicting the time-concentration of marbofloxacin in serum of normal foals after a single intravenous (D) and intramuscular (□) injection of 5 mg/kg b wt. (n = 6).

concentration (Cmax/MIC) ratio and the area under the 24-h serum concentration-time curve/MIC (AUC0_24h/MIC) ratio have been proposed to predict the antimicrobial efficacy of fluoroquinolones in vivo (Turnidge, 1999; McKellar et al., 2004). The PD efficacy of marbofloxacin was determined by calculating the Cmax/MIC and AUC/MIC ratios following IM administration using the hypothetical MIC90 of marbofloxacin against Enterobacteriaceae 0.027 mg/ml (Bousquet-Melou et al., 2002; Peyrou et al., 2004).

3. Results

The mean serum concentration time courses of marbofloxacin after intravenous and intramuscular administration are depicted in (Fig. 1). Pharmacokinetic parameters are showed in (Table 1). After intravenous administration of 5 mg/ kgb. wt., the marbofloxacin serum concentration time data fit two-compartment open model. The distribution half-life, elimination half-life, mean residence time of marbofloxacin after intravenous injection were 0.27, 6.4, 6.8 h. Following intramuscular administration, the drug absorbed at a fast rate

as indicated by short absorption half-life (t0.5(ab)) of 0.26 h. The drug was eliminated at a slow rate with an elimination halflife t0 5(el) of 7.16 h. The extent of serum protein binding was 27.5%.

Cp° concentration at zero time (immediately after single IV injection); A, B zero-time intercepts of the biphasic disposition curve; a, b hybrid rate constants representing the slopes of distribution and elimination phases, respectively; k12 firstorder constant for transfer from central to peripheral compartment; k21 first-order constant for transfer from peripheral to central compartment; Kel elimination rate constant; t0.5(a) distribution half-life; t0.5(b) elimination half-life; MRT mean residence time; AUC0-24 area under serum concentration-time curve; AUMC area under moment curve; Vc apparent volume of the central compartment; Vdss volume of distribution at steady state; ClB total body clearance. kab first-order absorption rate constant; Cmax maximum serum concentration; Tmax time to peak serum concentration; t0.5(ab) absorption half-life; t0.5(e]) elimination half-life; MAT mean absorption time; F fraction of drug absorbed systemically after IM injection.

4. Discussion

Data on the pharmacokinetics of marbofloxacin in equines are limited, and specific pharmacokinetic data for foals are lacking. Therefore, foals were treated with marbofloxacin at the recommended dose of 5 mg/kgb. wt. either IV or IM. The study revealed that serum marbofloxacin concentrations versus time decreased in a bi-exponential manner following intravenous injection, demonstrating the presence of distribution and elimination phases and justifying the use of two-compartment open model. This finding is in agreement with other pharmacokinetic study of the drug in calves (Ismail and El-Kattan, 2007). Serum concentration profiles showed a rapid initial distributive phase, followed by a slower elimination phase with an estimated mean elimination half-life of 6.4 h. This finding is similar to that recorded for the drug in horse

Table 1 - Pharmacokinetic parameters of marbofloxacin following a single intravenous (IV) and intramuscular (IM)

administration of 5 mg/kg in foals (n = 6).

Parameter Unit IV Parameter Unit IM

Cpo mg ml-1 4.1 ± 0.04 C ^max mg ml-1 1.14 ± 0.02

A mg ml-1 2.6 ± 0.01 T max h 1.3 ± 0.004

B mg ml-1 1.5 ± 0.04 Kab h-1 2.7 ± 0.02

a h-1 2.6 ± 0.05 Kel h-1 0.10 ± 0.003

ß h-1 0.11 ± 0.002 t0.5(ab) h 0.26 ± 0.001

K12 h-1 1.4 ± 0.02 t0.5(el) h 7.16 ± 0.11

K21 h-1 1.04 ± 0.04 AUC0-24 mg*h/ml 12.6 ± 0.31

Kel h-1 0.27 ± 0.004 AUMC mg*h-2/ml 96.2 ± 3.4

t0.5(a) h 0.27 ± 0.005 MRT h 8.01 ± 0.21

t0.5(ß) h 6.4 ± 0.08 MAT h 1.21 ± 0.22

Vc L kg-1 1.2 ± 0.007 F % 85.7 ± 0.09

Vdss L kg-1 2.3 ± 0.09 Cmax/MIC - 42.2 ± 0.27

C1b L kg-1 h-1 0.34 ± 0.003 AUC/MIC - 466.7 ± 11

MRT h 6.8 ± 0.12

AUC0-24 mg*h/ml 14.7 ± 0.27

AUMC mg*h-2/ml 94.84 ± 2.9

7.56 h (Bousquet-Melou et al., 2002). In this respect, fluoroquinolones have a long serum half-life making them suitable for once or twice a day administration (Vancutsem et al., 1990). The distribution of marbofloxacin in the body of foals recorded in this study was more than unity (>one L/kg) following intravenous injection (2.3 L/kg), indicated that the drug was extensively distributed to extra-vascular tissues and this result supported by Baggot (1978). In the present study, the total body clearance (Cltot) 0.34 L/kg/h agreed with that reported in horse 0.25 L/kg/h (Bousquet-Melou et al., 2002).

Following intramuscular administration, the drug absorbed at a fast rate as indicated by an absorption half-life (t0.5(ab)) of 0.26 h. The pharmacokinetic properties of fluoroquinolones include rapid absorption (Roland et al., 1995). This maybe due to the result of continued absorption of marbofloxacin from the site of intramuscular administration during the elimination phase, thereby, prolonging the t0 5(el) of the drug. Absorption limits drug elimination (Gibaldi and Perrier, 1982). The drug was eliminated at a slow rate with an elimination half-life t0 5(el) of 7.16 h. Also, this result supported by longer MRT of 8.01 h. The systemic bioavailability of marbofloxacin after IM administration was 85.7%, similar to that reported in horse 87.9% (Carretero et al., 2002). These values indicates high rate of absorption of the drug from that injection site. The in vitro protein binding tendency of marbofloxacin to foal's serum proteins was 27.5%. This indicated that the drug is slightly bound to serum proteins. It was stated that fluo-roquinolones binding to serum proteins is relatively low up to 30% (Wise et al., 1984).

The minimum inhibitory concentrations (MICs) of marbo-floxacin against foal's bacterial isolates have not yet been determined. The MIC of the drug was recorded to be 0.027 ug ml-1 against Enterobacteriaceae (Bousquet-Melou et al., 2002; Peyrou et al., 2004). Fluoroquinolones are active against bacterial pathogens in a concentration-dependent manner. Various empirical PK/PD ratios have been proposed to predict the success or failure of therapy. The effective use of the flu-oroquinolones against clinically important animal pathogens is dependent on designing dosages that attain serum Cmax/ MIC ratios of 10:1 or AUC/MIC ratios of 125:1 (Walker, 2000; Toutain et al., 2002). Marbofloxacin PK/PD integration after IM administration revealed values for Cmax/MIC and AUC/MIC ratios of 42.2 and 466.7 which indicate the excellent PD characteristics of the drug in foals.

The use of other fluoroquinolones has been associated with arthropathy in young animals of various species including foals (Vivrette et al., 2011), thus additional studies are necessary to confirm that marbofloxacin does not cause arthropathy before its use can be recommended in foals.

In conclusion, a dose of 5 mg of marbofloxacin/kg administered as a single dose once daily could be useful in the treatment of diseases caused by Enterobacteriaceae in foals.

Acknowledgments

The authors would like to thank professor Dr. H. A. ElBanna, Pharmacology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt, for comments on the manuscript.

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