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Pharmacokinetics of doxycycline in broiler chickensA. Anadón a , M. R. Martinez‐Larrañaga a , M. J. Diaz a , P. Bringas a , M. C. Fernandez a , M.

L. Fernandez‐Cruz a , J. Iturbe a & M. A. Martinez a

a Departamento de Toxicología, Instituto de Farmacología y Toxicología, CSIC, Facultad deVeterinaria, Universidad Complutense de Madrid, 28040, Madrid, Spain

Available online: 12 Nov 2007

To cite this article: A. Anadón, M. R. Martinez‐Larrañaga, M. J. Diaz, P. Bringas, M. C. Fernandez, M. L. Fernandez‐Cruz, J.Iturbe & M. A. Martinez (1994): Pharmacokinetics of doxycycline in broiler chickens, Avian Pathology, 23:1, 79-90

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Avian Pathology (1994) 23, 79-90

Pharmacokinetics of doxycycline in broilerchickens

A. ANADÓN, M. R. MARTINEZ-LARRAñAGA, M. J. DIAZ,P. BRINGAS, M. C. FERNANDEZ, M. L. FERNANDEZ-CRUZ,

J. ITURBE & M. A. MARTINEZ

Departamento de Toxicología, Instituto de Farmacología y Toxicología, CSIC,Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid,

Spain

SUMMARY

Doxycycline was given to two groups of eight chickens at a dose of 20 mg/kg of bodyweight, intravenously (i.v.) or orally. Plasma concentration was monitored serially for12 h after each administration. Another group of 30 chickens was given 20 mg/kgorally every 24 h for 4 days, and plasma and tissue concentrations determinedserially after the last administration. Concentrations of doxycycline were measuredusing high-performance liquid chromatography. Pharmacokinetic variables werecalculated, using a two-compartment open model. The elimination half-life and themean residence time for plasma were 6.03 ± 0.45 and 7.48 ± 0.38 h, respectively,after oral administration and 4.75 ±0.21 and 2.87 ±0.11 h, respectively, after i.v.administration. After single oral administration, doxycycline was absorbed rapidly,with Tmax of 0.35 ± 0.02 h. Maximum plasma concentration was 54.58 ± 2.44 μ/ml.Oral bioavailability of doxycycline was found to be 41.33 ± 2.02%. Doxycycline waswidely distributed in tissues and considerable concentrations were found followingoral administration of 20 mg/kg on four successive days. The results indicate thatdoxycycline concentrations were cleared slowly and were at or below the accepteddrug tolerance levels in the marker tissues within 5 days after dosing.

INTRODUCTION

Doxycycline (a-6-deoxy-5-hydroxytetracycline) is a 'second generation' tetracy-cline mainly active against Gram-positive and Gram-negative aerobic and anaero-bic bacteria. Spirochetes, Mycoplasma species, Rickettsia species, Chlamydiatracomatis and C. psittaci, Ureaplasma urealyticum, Erlichia species and Anaplasmaspecies also demonstrate good susceptibility (Riond and Riviere, 1988). Doxycy-cline has a low affinity for calcium and is relatively more stable in aqueoussolution (Fabre et al, 1971; Welling et ah, 1977). It has a high relative liposolu-bility (5- to 10-fold increases in relation to older tetracyclines) which readilycompensates for the high protein binding (Barza et al, 1975; Fourtillan &

A preliminary report of this study was presented at the EuroResidue II, Conference of Residues ofVeterinary Drugs in Food, Veldhoven, The Netherlands, May 3-5, 1993.

Received 13 April 1993; Accepted 24 June 1993.

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80 A. ANADON ETAL.

against staphylococci, streptococci and anaerobic bacteria (English, 1966;Williamson, 1968; Chow et al, 1975). All these characteristics support the notionthat doxycycline may have therapeutic usefulness in veterinary medicine.

Since doxycycline was introduced into modern drug therapy by Schach VonWittenau & Delahunt (1966) many of its pharmacokinetic and pharmacodynamiccharacteristics have been studied in detail mainly in humans (Fabre et al, 1971;Saux et al, 1981; Cars and Ryan, 1988). Doxycycline has several importantadvantages over other tetracycline analogues: absorption is almost complete,tissue penetration is good, elimination is slower necessitating only one daily dose,the elimination rate is irrespective of renal function and more than 90% of thedose is recovered as undegraded drug from urine and faeces.

Although few pharmacokinetic studies have been done in birds, doxycycline isoften used to treat avian infectious diseases such as colibacillosis, salmonellosis,staphylococcosis, mycoplasmosis and chlamydiosis, (George et al, 1977; Jakoby,1979; Gylstorff et al, 1984; Goren et al, 1988; Dorrestein et al, 1990). Thepurpose of the present study was to determine the pharmacokinetic values ofdoxycycline hydrochloride in broiler chickens so that rational therapeutic regi-mens may be formulated. The potential tissue residues were also evaluated inorder to establish the safety of doxycycline in this food-producing animal speciesin the context of public health.

MATERIALS AND METHODS

Chickens and protocol

Forty-six 40-day-old 2.5 kg male broiler chickens (Hubbard X Hubbard) werepurchased at a poultry farm and placed individually in cages in the animal houseof this laboratory 1 week before administration of the medication. Clinical signsof disease were not apparent. The animal house was maintained at 25 ± 2°C andat 45 to 65% humidity. Food and water were supplied ad libitum.

Experimental design

Birds were allotted to three groups. Groups 1 and 2 (eight chickens/group) weregiven single oral or intravenous (i.v.) administered doxycycline at 20 mg/kg bodyweight. Chickens of group 3 (n = 30) were given 20 mg of doxycycline/kg orallydaily for 4 consecutive days. Doxycycline hydrochloride was dissolved in distilledwater to a total volume of 0.5 or 2 ml prior to i.v. or oral administration,respectively. Doxycycline was administered i.v. in the right brachial vein or orallydirectly into the crop, using a thin plastic tube attached to a syringe. Food waswithheld for 12 h before each oral dosing.

For chickens of groups 1 and 2, blood samples were drawn via a cannula fromthe left brachial vein into heparinized syringes at 0.25, 0.33, 0.5, 1, 2, 4, 6, 8 and12 h after drug administration. Plasma was separated after centrifugation andstored at — 20°C until assayed for doxycycline concentration.

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PHARMACOKINETICS OF DOXYCYCLINE IN BROILERS 81

Group 3 chickens were killed by exsanguination (six chickens time) at 12, 24,48, 72 and 120 h after the last doxycycline dose. Blood, kidney, liver, lung andmuscle samples were obtained, carefully weighed and kept at — 20°C untilassayed.

Doxycycline assay

The concentration of doxycycline was measured using high-performance liquidchromatography (HPLC) (Bocker, 1980). Plasma, muscle, liver and kidneysamples were separately extracted. Plasma samples (0.5 ml) were mixed with0.5 ml 0.03M H3PO4; after 15min, 2 ml acetonitrile-buffer (0.01M NaH2PO4,pH 2.4) (50:50) was added. Five minutes later most of the precipitated proteinswere spun down (2500 g for 10 min), and the supernatant collected and frozen( - 20°C) until HPLC assay. Tissue sample was homogenized in ice-cold 0.03 MNaH2PO4 (1 part organ + 4 parts buffer) ultrasonically (1 min at 2.5 A using atitanium probe on a Labsonic U, B. Braun-Biotech SA). After 15 min, 1 ml of thehomogenate was mixed with 2 ml acetonitrile-buffer (0.01M NaH2PO4, pH 2.4)(50:50) and centrifuged (2500^ for 10 min). For the chromatographic analysis,20- or 100 fi\ aliquots of the supernatant were injected into the HPLC system(model LC-6A with UV spectrophotometric detector model SPD-6A and dataprocessor model Chromatopac CR-6A, Shimadzu) equipped with Lichrosorb RP8

column (particle size 5 /an; 15 X 0.4 cm) (Merck). The mobile phase was 0.01MNaH2PO4 in water-acetonitrile, 73:27, pH 2.4, and flow-rate of 1.5 ml/min wasused. Chromatography was performed at 25 ± 2°C with detection at 357 nm.Peak areas in the sample chromatograms were quantitated by use of the externalstandard technique, using a standard solution of doxycycline as reference. Thestandard curves were linear between 0.025 and 5 /*g/ml. The method used wasselective for the substance analysed; endogenous interference was not observed onchromatograms. The recovery of doxycycline from plasma and tissues was 98%when the doxycycline concentration was not higher than 100 ^g/ml. The lowerdetection limit was 25 ng/ml. The intra-and inter-assay coefficients of variationwere < 5 % .

Data analysis

Plasma concentration-time data were fitted to a two-compartment open model forkinetic analysis. Pharmacokinetic variables were obtained by use of an extendedleast-squares nonlinear regression programme (Sheiner, 1981). The plasmacurves of doxycycline after oral and i.v. administration were obtained for eachchicken and fitted to the following exponential equations:

Where C is the plasma concentration, Au A2 and A3 are mathematical

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82 A. ANAD6N ETAL.

coefficients; a is the hybrid rate constant for the distribution phase; /?, is thehybrid rate constant for the terminal elimination phase; and Kn is the first-orderabsorption rate constant. These equations were chosen by use of the minimalAkaike information criterion estimation (Yamaoka et a/., 1978). The error modelchosen to estimate the curve-fitting variables was proportional to the power ofprediction. The absorption half-life (tQ, the half-life at a phase (tl«), the half-lifeat P phase (tip), the distribution rate constants for transferring the drug from thecentral to the peripheral compartment (K^) and from the peripheral to the centralcompartment (K2\) and the elimination rate constant (Ki0) were calculated bystandard equations (Baggot, 1977).

After oral or i.v. administration, the areas under the concentration-time curves(AUC) were calculated as follows:

AUC = (AJa)

or

The total plasma clearance

[CL = (dose/kg) X FIA UC

or

CL = (dose/kg)/AUC]

The mean residence time

l) X 1/AUC

or

MRT= (AM +A2/02) X 1/AUC].

The apparent volume of distribution [V^tm) = (dose/kg) XF/AUCX /} orPd(arca) = (dose/kg)//J t/C X /J] and at steady state (only for i.v. administration,

The maximum concentration in plasma after oral administration (Cmax) and thetime needed to reach Cm!a(Tmix) were also evaluated. The oral bioavailability ofdoxycycline was calculated from the ratio between the value of AUCon\ for eachchicken and the mean value of AUCw for the eight chickens used in the i.v.administration study, F= (AUCO^/AUCJV). Complete absorption was determinedon the basis of AUCiv, which represents the mean AUC for the eight chickens towhich doxycycline was administered. Because of the small individual variation inAUCw and the fact that the same eight chickens were not available for oral andi.v. studies, the mean AUCjy, rather than AUCjy for each chicken, was used toestimate bioavailability after oral administration. Mean pharmacokinetic variableswere obtained by averaging the variables calculated for drug disposition after eachadministration in each chicken. Differences in pharmacokinetic data betweendosing routes were analyzed statistically by the Mann-Whitney £7-test. Differ-

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PHARMACOKINETICS OF DOXYCYCLINE IN BROI1JERS 83

1co

rati

c

400-

200-

100--

4 0 -

2 0 -

1 0 -

4 -

2 -

I6

Time (h)

110

I11 12

Figure 1. Plasma concentrations of doxycydine after (O) single oral or (9) i.v. administrationof 20 mg/kg. Data are expressed as mean ± SEM values for eight chickens. Symbols without barsindicate that the SEM is within the symbols.

ences of P< 0.05 were considered significant. All data were tabulated as mean ±SEM.

RESULTS

The mean plasma concentrations of doxycycline after a single oral or i.v. dose of20 mg/kg are shown in Figure 1. Following oral and i.v. administration, theplasma concentration-time curve exhibited a biphasic decline. A good fit ofobserved data to a two-compartment open model was obtained. The values of thekinetic parameters which described the absorption and disposition kinetics ofdoxycycline are given in Table 1.

Concentrations greater than 1 jig/ml (potential therapeutic value) were main-tained for at least 12 h post oral administration. The values for ria and 7 ^ inplasma were 0.109 ± 0.008 and 0.35 ± 0.02h, respectively. The maximum con-centration for the 20 mg/kg dose was 54.85 ± 2.44/ig/ml. Bioavailability ofdoxycycline after oral administration was 41.33 ± 2.02% (Table 1).

Doxycycline was distributed more quickly after i.v. than after oral dosing, thedistribution half-life (fi ) being 0.23 ± 0.01 and 0.40 ± 0.04 h, respectively; thesevalues were significantly (P< 0.05) different.

Doxycycline levels in plasma declined slowly (Figure 1) and the total plasmaclearance was 0.0401/h/kg (Table 1) irrespective of the dosing route. The i.v.elimination half-life (tip) was smaller than that for oral administration (P< 0.05).This difference is probably the result of continued absorption of doxycycline fromthe gastrointestinal tract during the elimination phase, thereby, prolonging the tipof the drug.

The mean tissue concentrations after daily oral administration are given in

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Table 1. Doxycycline pharmacokinetic variables in eightchickens aftersingle oralori.v. administration of 20 mg/kg

of body weight

Variable

Ai O«/ml)A2 Oug/ml)A3 (jig/ml)a(h"')/?(h-')*T.(h-')^(h)^(h)ti.(h)KdC a) (I/kg)VdM (I/kg)KnCh"1)Ki, (h'1)^io (h'1)

/lt/C (mg/h/1)P(%)MRTQOCL (1/h/kg)/C12/K21

•^12/^10

K21/JC10Cmax (/xg/ml)7*max(h)

Route of administration

OralMean ± SEM

90.46 ± 8.7022.25 ±2.59

128.10 ±12.771.81 ±0.140.12 ±0.016.55 ±0.450.40 ±0.046.03 ± 0.450.11 ±0.010.33 ± 0.02

0.98 ±0.100.55 ± 0.060.40 ± 0.02

214.21 ± 10.4641.33 ±2.02

7.48 ± 0.380.040 ± 0.001

1.93 ±0.152.45 ± 0.211.43 ±0.20

54.58 ± 2.440.35 ± 0.02

intravenousMean ± SEM

945.01 ±97.0830.78 ±4.20

2.99 ±0.110.15 ±0.01

0.23 ±0.01*4.75 ±0.21*

0.28 ± 0.020.11 ±0.011.02 ±0.060.24 ± 0.021.87 ±0.09

518.26 ±40.44

2.87 ±0.11*0.040 ± 0.0034.37 ± 0.330.56 ±0.050.13 ±0.02

*Significant (P< 0.05) difference between dosing routes.

Table 2. Plasma concentration of doxycycline at 12 h after the last dose was thesame whether the drug was given once or 4 times. The tissue-to-plasma concen-tration ratios (calculated 12 h after dosing) were for kidney, 0.53 ± 0.05; for lung,0.50 ± 0.07; for liver, 0.35 ± 0.04 and for muscle, 0.23 ± 0.03. Doxycycline waseliminated slowly from tissues. It was estimated that mean tissue doxycyclineconcentrations of 0.028 to 0.20 /xg/g persisted for 5 days after treatment(Table 2).

DISCUSSION

Although the pharmacokinetic variables of doxycycline have been studied inmammals the drug's kinetic profile in broiler chickens has received minimalinvestigation. Its disposition after i.v. or oral administration in chickens could bedescribed adequately by a two-compartment open model. Experiments performedin mammals (Ziv & Sulman, 1974; Michel et al, 1984; Jha et al., 1989; Riond etal, 1989) have led to the same conclusion. Disappearance of the drug from theplasma of chickens was characterized by an initial rapid distribution phase

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PHARMACOKINETICS OF DOXYCYCLINE IN BROILERS

Table 2 . Tissue concentrations of doxycycline inchickens after oral doses of 20 mg/kgfor 4 days

85

Tissue

Kidney

Liver

Lung

Muscle

Time afterthe last dose

12hI d2 d3 d5d

12hI d2 d3 d5 d

12 hI d2 d3 d5d

12 hI d2 d3 d5 d

Doxycycline

3.01 ±0.361.92 ±0.331.50 + 0.280.93 + 0.110.17 ±0.03

1.93 ±0.200.90 + 0.140.87 ±0.110.54 ±0.110.12 ±0.03

2.54 ± 0.251.68 ±0.220.77 + 0.120.12 + 0.020.03 ± 0.005

1.32 + 0.161.18 + 0.230.69 ± 0.090.26 ±0.100.06 + 0.02

* Each value is the mean ± SEM for sixchickens.

followed by a slower elimination phase. Doxycycline distributed very rapidly inbody fluids and tissues as evidenced by the high values for distribution rateconstant (short distribution half-life) and the high values of K12/K21 (Table 1).Doxycycline is highly lipophilic and would be expected to be distributed widely inthe chicken. Nevertheless, the V^m*) of 0.28 ± 0.02 I/kg determined in the presentstudy was much lower than that reported for other species: 0.75 I/kg in adulthumans (Raghuram & Krishnaswamy, 1982), 1.38 I/kg in calves (Riond et al,1989), 1.5 to 3.5 I/kg in dogs (Michel et al, 1979), 2.28 I/kg in cows and ewes(Ziv & Sulman, 1974), 4.5 to 7 I/kg in rats (Michel et al, 1984) and 9.78 I/kg ingoats (Jha et al., 1989). The lower value of apparent volume of distribution foundin the present study may be attributed to higher plasma protein binding, as wellas a lower gut reabsorption of drug in the chicken. Additional studies will benecessary to clarify this hypothesis. The doxycycline salt used also could affect theresult (Saux et al, 1981; Michel et al, 1984).

Doxycycline has a shorter tip in chickens than in other domestic species.Qualitative and quantitative differences in dosage and drug elimination may havecontributed to this result. Metabolism of doxycycline does not seem to be thecause of the differences in drug elimination among species. Photodiode arraydetection of an HPLC column effluent and mass-spectrometric analyses of serum

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86 A. ANAD6N ETAL.

and urine of calves, pigs, cats and dogs confirmed studies in man, whichsuggested that doxycycline is not metabolized (Fourtillan et al, 1980; Nelis & DeLeenheer, 1981; Riond et al, 1989, 1990; Riond & Riviere, 1990). The elimin-ation half-life (tip) found in chickens was similar to that recorded in young pigs(Riond et al, 1990) following an i.v. dose of 20 mg/kg. This may be attributed tothe similar volume of distribution obtained in chickens and young pigs. If theextent of binding to plasma proteins is similar in different species, it may bepostulated that in chickens and young pigs less drug binds to tissue or, possibly,there is less intracellular penetration. The extent of doxycycline binding tochicken serum proteins has not been tested.

The tip of doxycycline was longer than the tty of tetracycline (65 mg/kg in 2.7 h)obtained in broilers (Anadon et al, 1985).

After oral administration, doxycycline was rapidly, but only partially, absorbed.Average bioavailability of 20 mg/kg was 41%; lower than that (90-95%) found inmice and humans (Bocker & Estler, 1981; Fourtillan et al, 1980). The meanmaximum plasma concentration of 54.58 fig/ml reported here after the single oraladministration of 20 mg/kg was greater than the value reported by Archimbault etal (1983) in laying-hens (5.3 /ig/ml) after oral administration of 10 mg/kg. On theother hand, the mean T"max of doxycycline was 0.35 h in chickens, less than thatestimated in laying hens (Archimbault et al, 1983) or rats and humans (Michelet al, 1984). Considering therapeutic ranges reported in birds (Wachendorfer,1973; Goren et al, 1988) and in vitro minimal inhibitory concentrations ofsusceptible Gram-negative and Gram-positive organisms (Riond & Riviere, 1988)an approximate target concentration could be between 0.5 and 4 /zg/ml. In ourstudy, the plasma doxycycline concentration at 12 h for the 20 mg/kg dosage was5.29 ± 0.30 /ig/ml. On this basis, the plasma doxycycline concentration achievedafter oral administration of 20 mg/kg/day, should be appropriate for control ofavian diseases. The high peak blood concentrations ( > 50 /ig/ml) might alsosuggest it could be used effectively at a lower dose.

Previous studies have shown that doxycycline is readily available for tissuedistribution (Schach Von Wittenau & Delahunt, 1966; Bocker & Estler, 1981;Michel et al, 1984). In this study, high concentrations were found in kidney,liver, lung and muscle after a dosing regimen of 20 mg/kg daily for 4 days.Doxycycline is one of the most lipid soluble tetracycline derivatives (Cunhua etal, 1982). However, in the chicken we found that levels in kidney, liver, lung andmuscle were lower than the concurrent plasma levels 12 h after dosing. Thisfinding disagreed with that reported in rabbit by Cars and Ryan (1988) whofound concentrations in excess of serum levels in muscle. Thus, it may be that thedegree of tissue penetration of doxycycline in chickens is lower than in otherspecies.

Doxycycline is usually administered orally in chickens; thus, we studied adosing regimen of 20 mg/kg day for 4 days to estimate tissue-depletion ofdoxycycline. Substantial concentrations of doxycycline were still detected at 5days after termination of treatment.

In conclusion, doxycycline has useful pharmacokinetic characteristics for effec-

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PHARMACOKINETICS OF DOXYCYCLINE IN BROILERS 87

tive treatment of infections in poultry. In the chicken, it has been found to beabsorbed after oral administration and a therapeutic concentration is achieved inplasma. For oral administration of 20 mg/kg on four successive days, a withdrawaltime of 5 days might be adequate to predict that the concentrations in edibletissues are below accepted drug tolerance levels of 0.600 fig/g in kidney, 0.300 /ig/g in liver and 0.100 /zg/g in muscle (EEC, 1993). From a public health viewpoint,it is important to consider this recommendation in the light of an overallrisk-benefit assessment for consumers of this food-producing animal.

ACKNOWLEDGEMENTS

This research was supported by the Comisión Interministerial de Ciencia yTecnología, Plan Nacional de Investigación Científica y Desarrollo Tecnológico,Programa Nacional de Salud y Farmacia, Project SAF 92-0203 and by theComunidad de Madrid, Project N° 172/92, Spain.

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PHARMACOKINETICS OF DOXYCYCLINE IN BROILERS 89

RESUME

Pharmacocinétique de la doxycycline chez le poulet de chair

Deux groupes de huit poulets de chair ont reçu une dose de 20 mg/kg de poids vif dedoxycycline par voie orale et par voie intraveineuse. Après chaque administration du médica-ment, les concentrations plasmatiques de doxycycline ont été évaluées à différents intervallesde temps, pendant 12 h. Un autre groupe de 30 poulets a été traité oralement avec 20 mg dedoxycycline/kg par 24 h, pendant 4 jours.Les concentrations plasmatiques et tissulaires de doxycycline ont été déterminées à différentsintervalles de temps par Chromatographie liquide haute performance. Les paramètres pharma-cocinétiques ont été calculés conformément à un modèle bicompartimental ouvert. La demi-vied'élimination et le temps moyen de persistance dans le plasma ont été respectivement de6,03 ±0,45 et de 7,48 ±0,38 h après administration orale et de 4,75 ±0,21 et 2,87 ±0,11 hrespectivement après administration intraveineuse. La doxycycline, après administration oraled'une dose unique, a été absorbée rapidement avec un T max de 0,35 ± 0,02 h. La concen-tration plasmatique maximale a été de 54,58 ± 2,44 μg/ml. La biodisponibilité orale de ladoxycycline a été de 41,33 ± 2,02 % et le produit a été largement distribuée dans les tissus. Desconcentrations importantes de doxycycline ont été observées lors de l'administration orale dedoxycycline à la dose de 20 mg/kg pendant 4 jours consécutifs. Ces résultats indiquent que ladoxycycline s'élimine lentement des tissus et que les concentrations étaient égales ou in-férieures aux niveaux de tolérance acceptés dans les tissus cibles dans les 5 jours suivantl'administration de la dernière dose.

ZUSAMMENFASSUNG

Pharmakokinetik von Doxycyclin bei MasthühnernDoxycyclin wurde zwei Gruppen von je acht Masthühnern in der Dosis von 20 mg/kg Kör-pergewicht intravenös (i.v.) oder oral verabreicht. Die Plasmakonzentration wurde nach jederApplikation 12 Stunden lang regelmäßig kontrolliert. Einer anderen Gruppe von 30 Hühnernwurde 4 Tage lang alle 24 Stunden 20 mg/kg oral verabreicht, und die Plasma- und Geweb-skonzentrationen wurden in regelmäßigen Abstünden bestimmt. Die Doxycyclin-Konzentra-tionen wurden mit Hilfe der HPLC gemessen. Die pharmakokinetischen Variablen wurden mitHilfe eines offenen Zwei-Kompartiment-Modells berechnet. Die Eliminations-Halbwertzeitund die mittlere Verweildauer im Plasma waren 6,03 ± 0,45 bzw. 7,48 ± 0,38 Stunden nachoraler Verabreichung und 4,75 ± 0,21 bwz. 2,87 ± 0,11 Stunden nach i.v. Applikation. Nacheinmaliger oraler Gabe wurde Doxycyclin rasch resorbiert, mit einer Tmax von 0,35 ± 0,02Stunden. Die maximale Plasmakonzentration betrug 54,58 ± 2,44 μg/ml. Die Bioverfügbarkeitvon oral verabreichtem Doxycyclin betrug 41,33 ±2,02%. Doxycyclin wurde weit in denGeweben verbreitet, und beträchtliche Konzentrationen wurden an den 4 Tagen nach oralerApplikation von 20 mg/kg nachgewiesen. Die Ergebnisse zeigen, daß Doxycyclin langsameliminiert wurde und die Konzentrationen in den ausgewählten Geweben innerhalb von 5Tagen nach der Applikation nicht über dem akzeptierten Verträglichkeitsniveau lagen.

RESUMEN

Farmacocinética de la doxiciclina en pollos broilerSe administró doxiciclina a dos grupos de ocho pollos broiler a una dosis de 20 mg/kg de pesocorporal por vía intravenosa (i.v.) y oralmente. Se registró la concentración plasmática aintervalos durante 12 horas tras cada administración del fármaco. Otro grupo de 30 pollosrecibió una dosis de 20 mg/kg de peso corporal por vía oral cada 24 horas durante 4 días y se

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9 0 A. ANADÓN ETAL. •

determinaron seriadamente sus concentraciones plasmáticas y tisulares tras la última adminis-tración. Se empleó para ello el método de cromatografia líquida de alta resolución. Secalcularon las variables farmacocinéticas empleando un model abierto bicompartimental. Lavida media de eliminación y el tiempo medio de residencia para el plasma fue de 6.03 ± 0.45y 7.48 ±0.38 h respectivamente, tras la administración oral y 4.75 ±0.21 y 2.87±0.11 h,respectivamente, tras la administración i.v. Después de una sola administración por vía oral, ladoxiciclina se adsorbió rápidamente, con T max0.35 ± 0.02 h. La concentración plasmáticamáxima fue de 54.58 ± 2.44 μg/ml. La biodisponibilidad de la doxiciclina vía oral fue de41.33 ± 2.02 %. La doxiciclina se distribuyó ampliamente en los tejidos y se encontraron unasconcentraciones elevadas cuando la doxiciclina se administró por vía oral (20 mg/kg) durante4 días consecutivos. Estos resultados indican que la doxiciclina se elimina lentamente de lostejidos, estando al nivel o por debajo de los niveles de tolerancia aceptados en los tejidosmarcadores a los 5 días de haber administrado la última dosis.

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