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Pharmacokinetics of Marbofloxacin After Oral Administration to EurasianBuzzards (Buteo buteo)Author(s): Marino García-MontijanoLV, Fernando GonzálezDVM, PhD, Samanta WaxmanDVM,PhD, Celia SánchezLV, J. Julio de LucasDVM, PhD, Manuel San AndrésDVM, PhD, and CasildaRodríguezDVM, PhDSource: Journal of Avian Medicine and Surgery, 17(4):185-190. 2003.Published By: Association of Avian VeterinariansDOI: http://dx.doi.org/10.1647/2001-033URL: http://www.bioone.org/doi/full/10.1647/2001-033

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185

Journal of Avian Medicine and Surgery 17(4):185–190, 2003q 2003 by the Association of Avian Veterinarians

Original Research

Pharmacokinetics of Marbofloxacin After OralAdministration to Eurasian Buzzards (Buteo buteo)

Marino Garcıa-Montijano, LV, Fernando Gonzalez, DVM, PhD,Samanta Waxman, DVM, PhD, Celia Sanchez, LV, J. Julio de Lucas, DVM, PhD,

Manuel San Andres, DVM, PhD, and Casilda Rodrıguez, DVM, PhD

Abstract: Marbofloxacin is a bactericidal fluoroquinolone developed exclusively for veterinarymedicine. The pharmacokinetic disposition of this drug was studied after oral administration of asingle dose (10 mg/kg) to 8 adult Eurasian buzzards (Buteo buteo). Plasma concentrations of mar-bofloxacin were measured during the 48-hour period after drug administration. A maximum plasmaconcentration of 3.70 mg/ml was achieved at 2.92 hours. Marbofloxacin was relatively slowly ab-sorbed after oral administration (absorption half-life of 1.57 hours) and demonstrated a high bio-availability (92.15%). The elimination half-life was 9.48 hours, and the mean residence time was10.65 hours. When using a minimum inhibitory concentration (MIC) breakpoint of 0.25 mg/ml, thecalculated antimicrobial efficacy of orally administered marbofloxacin was higher than the rangeconsidered optimal for a dosing regimen against pathogens with an equivalent MIC. A dosage of10 mg/kg administered once daily appears to be appropriate for the treatment of most infectionswith gram-negative bacteria that affect Eurasian buzzards.

Key words: marbofloxacin, pharmacokinetics, raptors, Eurasian buzzards, Buteo buteo

Introduction

Fluoroquinolone antimicrobial agents have beenused extensively in avian medicine because of theirbroad spectrum of activity and relative lack of ad-verse effects.1–3 Marbofloxacin, a fluoroquinolonedeveloped exclusively for use in veterinary medi-cine, exerts a bactericidal effect through inhibitionof DNA gyrase of a susceptible microorganism.4

Marbofloxacin has an antibacterial spectrum similarto or broader than that of other fluoroquinolones,including an excellent potency in vitro againstmembers of the Enterobacteriaceae, including Esch-erichia coli, and other gram-negative bacteria and

From AULAGA, Spanish Imperial Eagle Captive BreedingCentre Quintos de Mora, Ministerio de Medio Ambiente, Direc-cion General de Conservacion de la Naturaleza, Gran Vıa SanFrancisco 4-6, 28005, Madrid, Spain (Garcıa-Montijano); Depar-tamento de Toxicologıa y Farmacologıa, Facultad de Veterinaria,Universidad Complutense de Madrid, Avenida Puerta de Hierros/n, 28040, Madrid, Spain (Gonzalez, de Lucas, San Andres,Rodrıguez); Catedra de Farmacologıa, Facultad de Ciencias Ve-terinarias, Universidad de Buenos Aires, C/ Chorroarin 280,1427, Buenos Aires, Argentina (Waxman); and Centro de Re-habilitacion de Fauna Salvaje El Acebuche, 21.760, Matalascan-as, Huelva, Spain (Sanchez).

also has a marked postantibiotic effect. Marboflox-acin is especially effective against species of Pas-teurella, has good activity against Staphylococcusaureus and S intermedius (2 coagulase-positivestaphylococci), and also may be effective againstspecies of Mycoplasma and Pseudomonas. Marbo-floxacin is less active against species of Streptococ-cus.5

Pharmacokinetic studies of marbofloxacin dis-position in dogs demonstrated that a dosage of 2mg/kg PO q24h was able to maintain effective plas-ma activities for longer than enrofloxacin at a dos-age of 5 mg/kg PO q24h,6 indicating the potentialsuitability of marbofloxacin as an antibacterial ther-apy requiring only once-daily dosing. However, theelimination half-life (t1/2b) values found in othermammals (horses, goats, cows, ewes, and sows)were considerably shorter than those reported in thedog.7–10 We previously reported that intravenous ad-ministration of marbofloxacin to Eurasian buzzards(Buteo buteo) at a dose of 2 mg/kg resulted in ashorter t1/2b, higher clearance, and lower plasmaconcentration than the corresponding values indogs.11

186 JOURNAL OF AVIAN MEDICINE AND SURGERY

A limited number of antibiotic dosages for rap-tors have been established based on published phar-macokinetic studies. A broad-spectrum antibioticwith minimal or no adverse effects that could bedosed once daily would be ideal for treatment ofraptors. Oral treatment also would be expected toresult in less stressful management of the patientthan parenteral treatment. Marbofloxacin was usedorally, with dosing ranges varying from 9 to 15.2mg/kg q24h, in a clinical study involving differentspecies of birds of prey. No deleterious effects wereobserved.1,12 However, the pharmacokinetic behav-ior of marbofloxacin after oral administration inbirds of prey is unknown. Our goal was to examinethe pharmacokinetic disposition of a single oraldose of marbofloxacin in Eurasian buzzards.

Materials and Methods

Eight adult Eurasian buzzards of unknown sexand weighing 0.6–0.9 kg were selected for thisstudy. The birds were obtained from a wild popu-lation presented to Acebuche Wildlife Rehabilita-tion Center located in Donana National Park, Huel-va, Spain. All birds were housed in outdoor flightenclosures and were fed a diet of rabbit, quail, mice,and 1-day-old chicks 6 days per week. Water wasprovided ad libitum. No antibiotics or anthelminticswere administered for at least 2 months before thestart of the study. Criteria for selection of clinicallyhealthy birds included routine acceptance of dailymeals, maintenance of body weight, complete phys-ical examinations within reference limits, and com-plete blood count and plasma biochemistry valuesindicating no significant abnormalities.13

Birds were fasted for 24 hours before the start ofthe study. A suspension was formulated from 2 5-mg marbofloxacin tablets (Marbocyl, Vetoquinol,Lure, France) added to 3 ml of tap water. A gavagetube was used to administer the marbofloxacin sus-pension into the crop of each bird at a dosage of 10mg/kg followed by 3 ml of water. After removal ofthe tube, the birds were placed in their cages andobserved for regurgitation.

Seven blood samples were obtained from eachbird at scheduled times after drug administration.The birds were randomly divided into 2 groupsbased on sampling time. Four birds were sampledat 0, 0.25, 0.75, 2, 6, 12, and 36 hours, and theother 4 birds were sampled at 0, 0.5, 1, 4, 8, 24,and 48 hours after administration. At each sched-uled time, 1 ml of blood was collected from thecutaneous ulnar vein, by using a 25-gauge needleon a 2-ml heparinized syringe, and stored in pedi-atric lithium heparin tubes. Plasma was separated

immediately and stored at 2208C before being an-alyzed.

Plasma concentrations of marbofloxacin weremeasured by high-performance liquid chromatog-raphy based on modification of previously pub-lished methods.14 Statistical analysis was performedwith GraphPad Inplot 4.1 software, which is a com-bination of basic biostatistics, curve fitting, and sci-entific graphing (GraphPad Software Inc, San Die-go, CA, USA).

Pharmacokinetic parameters were estimated bycompiling the data from all individuals according tothe naive pooled data approach.15 A compartmentalpharmacokinetic analysis that used a nonlinearleast-squares regression was performed. Biexponen-tial and triexponential equations were fitted to plas-ma concentration-time data. Akaike’s informationcriterion, residual sum of squares, and analysis ofresidual’s plots were used to discriminate betweenmodels.16 The area under the curve from 0 to 48hours (AUCt) and from 0 to ` after dose (AUC`)administration and the mean residence time from 0to 48 hours (MRTt) and from 0 to ` (MRT`) wereanalyzed and determined by using a noncompart-mental pharmacokinetic approach. Pharmacokineticanalyses were performed with PcNonlin V 4.0 (SCISoftware, Lexington, KY, USA) and GraphPad In-plot 4.1 (GraphPad Software) software packages.

The calculated marbofloxacin peak concentration(Cmax) and AUC` were used to compute the esti-mates of antimicrobial efficacy indicators. The Cmax

to minimum inhibitory concentration (MIC) ratio(Cmax/MIC) and the area under the MIC to timecurve (AUC/MIC) were used to evaluate predicteddrug efficacy. A MIC breakpoint of 0.25 mg/ml wasused for these computations.

Results

Mean analytic recovery for marbofloxacin fromplasma was 90.57 6 4.66%. The quantification limitwas 0.017 mg/ml and the method was linear be-tween 0.017 mg/ml and 15 mg/ml. The interassayand intra-assay reproducibilities both were less than6% (coefficient of variation).

Plasma concentrations of marbofloxacin versustime after a single oral dose of 10 mg/kg are shownin Figure 1. The plasma concentration-time profilewas best described by an open 2-compartment mod-el with first-order input and output.

The pharmacokinetic parameters obtained aftercompartmental and noncompartmental analysis areshown in Table 1. The time at which the Cmax (3.70mg/ml) was achieved (tmax) was 2.92 hours. Mar-bofloxacin was relatively slowly absorbed after oral

187GARCIA-MONTIJANO ET AL—PHARMACOKINETICS OF MARBOFLOXACIN

Figure 1. Marbofloxacin concentrations versus time af-ter oral administration of marbofloxacin (10 mg/kg) to 8Eurasian buzzards.

Table 1. Pharmacokinetic parameters obtained after oraladministration of marbofloxacin (10 mg/kg) to 8 Eurasianbuzzards.

Pharmacokinetic parametersa Value

A (mg/ml)B (mg/ml)a 3 1024 (h21)b 3 1024 (h21)K12 3 1024 (h21)

26.201.780.910.202.28

K21 3 1024 (h21)K10 3 1024 (h21)t1/2abs (h)t1/2a (h)t1/2b (h)

3.331.221.572.109.48

tmax (h)Cmax (mg/ml)AUCt (mg · h/ml)AUC` (mg · h/ml)MRTt (h)MRT` (h)

2.923.70

45.4445.9910.0510.65

a A and B indicate the y intercept of a calculated curve duringthe distribution and elimination phase, respectively; a and b,first-order rate constants associated with distribution and elimi-nation phases, respectively; K12, transfer constant from com-partment 1 to compartment 2; K21, transfer constant from com-partment 2 to compartment 1; K10, elimination constant; t1/2abs,absorption-phase half-life; t1/2a, distribution-phase half-life; t1/2b,elimination-phase half-life; Cmax, peak drug concentration; tmax;time to Cmax; AUC`, area under the plasma concentration-timecurve; AUCt, area under the plasma concentration-time curvefrom time zero to last time (29 h); MRTt, mean residence timefrom time zero to last time; and MRT`, mean residence time.

administration, as indicated by an absorption half-life (t1/2abs) of 1.57 hours. The t1/2b and MRTt were9.48 and 10.05 hours, respectively. Marbofloxacinconcentrations remained higher than 1 mg/ml for atleast 12 hours after administration. When using anMIC breakpoint of 0.25 mg/ml, the Cmax/MIC ratiowas 14.8 and AUC/MIC was 181.75. No adverseeffects were observed during the study.

Discussion

Because very few published clinical trials andpharmacokinetic analyses are available to guidetherapy in birds of prey, the clinician has been facedwith the necessity of broad interspecies extrapola-tion of doses with no guarantee that these estimatesare efficacious.17,18 Based on a previous study,1 wedecided to investigate the disposition of marboflox-acin in Eurasian buzzards after a single oral dose.Marbofloxacin demonstrates bicompartmental be-havior after oral administration, in accordance withobservations in Eurasian buzzards after intravenousadministration.11 Similar results have been de-scribed in other species.7,9,10,19

In previous studies with birds of prey,1 no ad-verse effects were seen during therapy with orallyadministered marbofloxacin. In particular, no in-stances of vomiting occurred, as had been reportedwith enrofloxacin.3 Our observations in this studywere the same.

Marbofloxacin was relatively slowly absorbed af-ter oral administration, as reflected by a t1/2abs of 1.57hours and a tmax of 2.92 hours. Absorption time islonger in buzzards than the t1/2abs of 0.6 hours de-scribed in broiler chickens.20 Differences in the di-gestive system are known to cause marked differ-ences in the rate and extent of drug absorption inbirds treated via the oral route.21,22

Why larger doses of some orally administeredquinolones are required in birds to achieve a Cmax

and an MRT similar to those reported for lower dos-es in mammals is unclear. This has been postulatedto be caused by poor bioavailability or a more rapidelimination of these drugs in birds.23 The bioavail-ability of fluoroquinolones after oral administrationis somewhat higher for mammals than for birds anddepends on the specific agent administered.4,23 InEurasian buzzards, marbofloxacin showed high ab-sorption from the gastrointestinal tract. Previously,we had determined the pharmacokinetic behavior ofmarbofloxacin (2 mg/kg) after intravenous admin-istration to Eurasian buzzards.11 The AUC` de-scribed in our previous study was used to calculatethe bioavailability of marbofloxacin after oral ad-ministration. The value obtained was high (92.15%)but lower than that observed in dogs (105.3–107.8%).14 Low bioavailability (58%) after oral ad-ministration of marbofloxacin has been described inbroilers.20 Marbofloxacin administered orally toEurasian buzzards had a higher bioavailability thanenrofloxacin administered orally to red-tailed hawks(Buteo jamaicensis) (76%),24 houbara bustards(Chlamydotis undulata) (62.3%),21 and grey parrots

188 JOURNAL OF AVIAN MEDICINE AND SURGERY

Table 2. Mean pharmacokinetic parameters of orally administered fluoroquinolones in selected avian species.a

Species FluoroquinoloneDose

(mg/kg) MRT (h) t1/2b (h) Cmax (mg/ml) tmax (h)AUC

(mg · h/ml) Reference

Houbara bustardGreat horned owlRed-tailed hawk

Grey parrot

EnrofloxacinEnrofloxacinEenrofloxacinCiprofloxacinEnrofloxacin

1015155015

10.10——4.064.28

6.807.28.92.492.52

1.842.62.83.64—

0.667.15.40.92—

15.744.047.216.66.73

2124242825

Broiler chicken

Eurasian buzzard

DanofloxacinEnrofloxacinMarbofloxacinMarbofloxacin

5102

10

8.697.588.55

10.65

6.625.819.039.48

0.471.881.053.70

1.501.501.482.92

3.5314.426.71

45.99

272720

present study

a MRT indicates mean residence time; t1/2b, elimination-phase half-life; Cmax, peak drug concentration; tmax, time to Cmax; and AUC,area under the curve.

(Psittacus erithacus) (51%)25 and was similar to thatof enrofloxacin administered orally to pigeons (Co-lumba livia) (87–92%)26 and broilers (89.2%).27

In our study, the apparent distribution half-life ofmarbofloxacin was greater after oral administration(2.10 hours) than after intravenous administration(7.76 minutes).11 The elimination-phase parametersobtained after oral administration (t1/2b 5 9.48 hoursand MRT` 5 10.65 hours) also were greater thanthose observed after intravenous administration (t1/2b

5 4.11 hours and MRT` 5 5.79 hours),11 suggestingthe presence of a flip-flop phenomenon, that is, slowabsorption of the drug that affected its rate of elim-ination. The t1/2b of marbofloxacin (9.03 hours) afteroral administration in chickens at a dosage of 2 mg/kg was similar to that obtained in our study.20

Mean pharmacokinetic parameters for selectedfluoroquinolones orally administered in avian spe-cies are presented for comparison in Table 2. TheMRT of marbofloxacin administered orally to Eur-asian buzzards is greater than that of marbofloxacinand other fluoroquinolones orally administered toother avian species listed. The t1/2b of marbofloxacinadministered orally to Eurasian buzzards is greaterthan that of ciprofloxacin tablets (50 mg/kg PO) ad-ministered to red-tailed hawks (2.49 hours)28 andenrofloxacin oral solution administered to houbarabustards (10 mg/kg; 6.80 hours)21 and grey parrots(15 mg/kg; 2.52 hours).25 The t1/2b of enrofloxacinadministered orally to red-tailed hawks (15 mg/kg;8.9 hours)24 and great horned owls (Bubo virgini-anus; 15 mg/kg; 7.2 hours)24 was similar to thatobserved with marbofloxacin in our study. It is in-teresting to note that although the dose of enroflox-acin administered to each of the species listed wasgreater than the dose of marbofloxacin used in ourstudy,24 the Cmax and AUC values for enrofloxacinwere less than or similar to the corresponding val-ues for marbofloxacin. In addition, the tmax of orally

administered enrofloxacin was lower in these spe-cies than that of marbofloxacin in our study.24 Theseresults suggest that marbofloxacin may be an ac-ceptable alternative to other fluoroquinolones ad-ministered orally to birds.

Although no data have been published concern-ing the antibacterial activity of marbofloxacinagainst avian bacterial isolates, previous studieshave shown that in vitro and ex vivo bactericidalactivity of marbofloxacin against animal pathogenswas similar to or even better than that of enroflox-acin.6,29–31 Based on the available published reportsdiscussing the value of surrogate markers to predictclinical success, a Cmax/MIC ratio of 10 or an AUC/MIC ratio of 125–250 has been associated with op-timal bactericidal effect. High Cmax/MIC ratios alsohave been associated with a lower incidence of re-sistance development.32–34

To the authors’ knowledge, the MIC for marbo-floxacin against avian pathogens has not been re-ported in the literature, so we used MIC values forbacteria affecting dogs and cats.5 When using anMIC breakpoint of 0.25 mg/ml, the pharmacokineticparameters determined in our study, and the phar-macodynamic variables associated with an optimalbactericidal effect, an optimal dosage can be esti-mated. After oral administration, a single marbof-loxacin dose of 10 mg/kg gave a Cmax/MIC of 14.8and an AUC/MIC of 181.75. These values are high-er than the established ranges used to obtain an op-timal dosage for pathogens with an equivalent MIC.Some pathogens, such as Streptococcus species,Pseudomonas species, and S aureus, have an MICvalue higher than that mentioned above. A dosageof 10 mg/kg administered once daily appears to beappropriate for the treatment of most gram-negativeinfections that affect Eurasian buzzards.

In the absence of other studies, these resultsshould be viewed as preliminary and used only as

189GARCIA-MONTIJANO ET AL—PHARMACOKINETICS OF MARBOFLOXACIN

a guide for the clinical application of marbofloxacinin Eurasian buzzards.

Acknowledgments: We thank the Acebuche WildlifeRehabilitation Center staff for helping with the birds andMr Pablo Pereira for making our work in Donana pleas-ant. We also thank Mr Mariano Dıaz-Flores for his tech-nical assistance and Dr Ines Luaces for helping with ref-erences. Vetoquinol is acknowledged for kindly supply-ing the marbofloxacin used in the study. We also aregrateful to Jaime H. Samour and 3 anonymous reviewersfor helping to improve the manuscript.

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