Pharmacokinetics of amoxicillin clavulanic acid combination after intravenous and intramuscular administration to turkeys and chickens

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1 Avan Pathology ISSN: (Prnt) (Onlne) Journal homepage: Pharmacoknetcs of amoxclln clavulanc acd combnaton after ntravenous and ntramuscular admnstraton to turkeys and chckens Carlos M. Carceles, M. Soledad Vcente & Elsa Escudero To cte ths artcle: Carlos M. Carceles, M. Soledad Vcente & Elsa Escudero (1995) Pharmacoknetcs of amoxclln clavulanc acd combnaton after ntravenous and ntramuscular admnstraton to turkeys and chckens, Avan Pathology, 24:4, , DOI: / To lnk to ths artcle: Publshed onlne: 12 Nov Submt your artcle to ths journal Artcle vews: 1083 Vew related artcles Ctng artcles: 8 Vew ctng artcles Full Terms & Condtons of access and use can be found at

2 Avan Pathology (1995) 24, Pharmacoknetcs of amoxclln-clavulanc acd combnaton after ntravenous and ntramuscular admnstraton to turkeys and chckens CARLOS M. CARCELES, M. SOLEDAD VICENTE & ELISA ESCUDERO Department of Pharmacology, Faculty of Veternary Medcne, Unversty of Murca, Campus de Espnardo, Murca, Span SUMMARY The pharmacoknetc behavour of amoxclln/clavulanc acd (4:1) combnaton was studed after ntravenous and ntramuscular admnstraton of sngle doses (25 mg/kg body weght) to 15 turkeys and 15 chckens. The objectve was to determne whether there are dfferences between turkeys and chckens n the dsposton knetcs of amoxclln and clavulanc acd. The plasma concentratons-tme data were analysed by compartmental pharmacoknetc and non-compartmental methods. The dsposton curves for both drugs after ntravenous admnstraton were best descrbed by a two-compartment open model n turkeys and chckens. The apparent volumes of dstrbuton of amoxclln and clavulanc acd were smlar n the two speces. The body clearances of amoxclln and clavulanc acd n turkeys were sgnfcantly slower than n chckens. The elmnaton half-lfe of amoxclln was smlar n turkeys (1.12 ±0.09 h) and chckens (1.03 ±0.11 h) after ntravenous admnstraton, but that of clavulanc acd dffered sgnfcantly (P<0.05) between turkeys (1.12 ±0.03 h) and chckens (0.98 ± 0.05 h). After ntramuscular admnstraton both drugs had a sgnfcantly longer half-lfe (P<0.05) n turkeys and chckens than that after the ntravenous treatment. The boavalablty after the ntramuscular njecton was hgh and smlar wth both drugs, but hgher values were obtaned for chckens than turkeys. INTRODUCTION Amoxclln/clavulanc acd combnaton s a broad spectrum antbacteral preparaton whch offers certan advantages over amoxclln alone: (a) resstance aganst a wde varety of ß-lactamases, (b) low toxcty, and (c) usefulness for oral and ntramuscular admnstraton. The formulaton has been especally useful n anmals for treatng bacteral nfectons of the urnary and respratory tracts, and of the skn (Alaman, 1991; Bywater et al, 1985; Senor et al., 1985). For correct dosage and dosng regmens of drugs t s essental to establsh pharmacoknetc data n each speces. As such pharmacoknetc studes n brds are rare, the clncan may have to extrapolate dosages from other speces. Such Receved 29 November 1994; Accepted 12 July /95/ Houghton Trust Ltd

3 644 C. M. CÁRCELES ETAL. an approach s potentally undesrable because napproprately low doses can lead to neffectve therapeutc blood or tssue levels and to ncreased chances of development of resstant mcro-organsms whle toxcty may result f the extrapolated dose s too hgh (Dorresten et al., 1984). Even though the effectve concentraton range of a drug may be the same n dfferent speces, systemc avalablty and values of the dsposton parameters may vary wdely (Baggot, 1977). In brds, the anatomy of the upper part of the almentary tract and the physology of dgeston are dfferent from mammals, and although absorpton processes wll be smlar, the ste and the rate of absorpton may vary. Addtonal complcatons are water solublty, stablty, palatablty, loss of actve drug due to nactvaton and dfferent water or feed ntake patterns among dfferent speces. Parenteral admnstraton s the most exact and effectve method of gvng drugs to brds, but for practcal reasons ths route s manly restrcted to ndvdual brds whch are dffcult to dose orally because of ther dsease status, or whch need nstant treatment. Parenteral treatments are most commonly admnstered ntramuscularly n the pectoral or leg muscles. The objectve of the present study was to nvestgate and compare the pharmacoknetcs of amoxclln/clavulanc acd (4:1) combnaton preparaton after ntravenous and ntramuscular admnstraton to turkeys and chckens n order to determne adequate dosage regmens. Anmals MATERIALS AND METHODS Ffteen 52-week-old Ncholas turkeys weghng ± 1.67 kg and weekold chckens (Hubbard X Hubbard) weghng 3.25 ± 0.97 kg were used. Healthy males and females were ncluded, and they had not receved antbotcs for 4 weeks pror to ths study. They were kept n wre-floored cages wth underlyng removable trays whch were cleaned daly. They had free access to water, a standard breedng food mx and sutable grt mneral. On the nght before each experment the brds were weghed and housed ndvdually wth free access to water and food. Study desgn The study was conducted n two phases. An aqueous soluton of amoxclln/ clavulanc acd (4:1 rato) was admnstered to the brds at a dosage of 25 mg/kg body weght (20 mg/kg of sodum amoxclln and 5 mg/kg of potassum clavulanate; Clavumox 11 njectable soluton, 1%; Antbótcos, S.A. Laboratores, Madrd, Span). In the frst phase the combnaton was njected nto 10 brds of each speces va the left vlnars ven and blood samples were collected from the contralateral ulnars ven nto heparnzed tubes at 0 (pretreatment), 0.05, 0.10, 0.15, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4 and 5 h. In the second phase the combnaton was njected nto fve brds of each speces n the pectorals muscle

4 KINETICS OF AMOXICIIUN/CLAVULANATE IN BIRDS 645 and the blood samples were collected at 0, 0.10, 0.15, 0.25, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 10 h. The samples were centrfuged at 1500 g for 15 mn and the plasma was stored for 1 day at 40 C untl assayed. Analytcal method Plasma concentratons of amoxclln and clavulanc acd were measured by hgh performance lqud chromatography (HPLC) usng a Waters System (Waters, Mlford, USA) equpped wth a 721 model ntegrator and the method of Foulstone & Readng (1982). The column used was a / Bondapack C 8 (Waters) wth a guard-pak precolumn wth the same fllng. The moble phase was 6% methanöl plus phosphate buffer wth the ph adjusted to 3.2 and the flow rate was 2 ml/mn. The concentratons were scanned by a u.v. detector at 227 nm for amoxclln and 311 nm for clavulanc acd. For clavulanc acd assay, the plasma samples were dervatzed (Foulstone & Readng, 1982) usng mdazole reagent (n 8.25 ml of dstlled water and wth ph adjusted to 6.8 by HC1). The lmts of detecton were 0.09 g/ml for amoxclln and 0.04 /g/ml for clavulanc acd. Pharmacoknetcs A pharmacoknetc computer programme (PCNONLIN) was used for analyss of plasma concentraton-tme data. Intal estmates were obtaned usng the ES- TRIP programme. The data were analysed on an ndvdual brd bass and usng a weghtng coeffcent of I/concentraton. Areas under the plasma concentratontme curves were calculated usng the trapezodal logarthmc method wth extrapolaton to nfnte tme. Boavalablty (F) was calculated by the method of correspondng areas, whch entals comparson of the total areas under the plasma concentraton-tme curves (AUC) obtaned after ntramuscular and ntravenous admnstraton: F= AUCJDose m AUdJDose v The symbols, equatons and defntons used for plasma pharmacoknetc studes were standard (Aronson et al, 1988). Statstcal analyss The usual statstcal parameters were calculated and the Kolmogorov-Smrnov test employed to verfy the homogenety of the data. The Mann Whtney test and the Student's r-test were used to test pharmacoknetc parameters for sgnfcant dfferences between turkeys and chckens (Powers, 1990).

5 646 C. M. CÁRCELES ETAL. 1! CO I 100-, I 1 - Amoxclln.v. o Amoxclln.m. Clavulanc acd.v. a Clavulanc acd.m. I o.h 0.01 I \ 5 6 Tme (h) T 10 Fgure 1. Mean plasma concentratons of amoxclln and clavulanc acd combnaton n turkeys followng sngle ntravenous or ntramuscular admnstraton at a dosage of 25 mg/kg (20 mg/kg of amoxclln and 5 mg/kg of clavulanc acd). RESULTS Mean plasma concentratons of amoxclln and clavulanc acd acheved by each route of admnstraton are plotted n Fgures 1 and 2 for turkeys and chckens, respectvely. The pharmacoknetc parameters (mean ± SD) based on compartmental pharmacoknetc analyss and non-compartmental methods are presented n Table 1 for turkeys and Table 2 for chckens. The followng mean equatons were obtaned after ntravenous admnstraton to turkeys: C = e (amoxclln) C= e l e ' (clavulanc acd) and after ntravenous admnstraton to chckens: C = e~ t e t (amoxclln) C= e t <r t (clavulanc acd) where concentratons are expressed n mg/1 and tme n hours. There were sgnfcant dfferences between turkeys and chckens n some of the pharmacoknetc parameters after ntravenous admnstraton. For amoxclln, the sgnfcant dfferences (P< 0.05) were n the dstrbuton rate constant (A), the half-lfe of the dstrbuton phase (t^) and the non-compartmental parameters: area under the concentraton-tme curve (AUC) and body clearance (Cl/F). For clavulanc acd, sgnfcant dfferences (P<0.05) were found n the dstrbuton (A) and elmnaton (l z ) rate constants, the half-lfe of the dstrbuton (t±x) and elmnaton phases (r^) and the non-compartmental parameters AUC, mean resdence tme (MRT) and Cl/F. In turkeys and chckens, no sgnfcant dfferences were found between amoxclln and clavulanc acd n the followng parameters: X z, t^xz» P» and MRT. In both speces, a sgnfcantly longer half-lfe (r^) of amoxclln and clavulanc acd was found after ntramuscular admnstraton compared to the ntravenous

6 KINETICS OF AMOXICIIJJN/CLAVULANATE IN BIRDS , Amoxclln.v. o Amoxclln.m. Clavulanc acd.v. o Clavulanc acd.m I I I 5 6 Tme (h) Fgure 2. Meanplasma concentratons of amoxclln andclavulanc acd combnaton n chckens followng sngle ntravenous or ntramuscular admnstraton at a dosage of 25 mg/kg (20 mg/kg of amoxclln and 5 mg/kg of clavulanc acd). Table 1. Pharmacoknetc parameters (mean±sd) descrbng the dsposton of amoxclln and clavulanc acd after ntravenous or ntramuscular admnstraton n turkeys (25 mg/kg, 20 mg/kg of amoxclln and 5 mg/kg of clavulanc acd) Intravenous route (n = 10) Intramuscular route (n = 5) Parameters Amoxclln Clavulanc Amoxclln Clavulanc *.(h-') A, (h" 1 ) A,(h-') «(h) tn 00 W (h) C m (mga) F,(l/kg) ^(1/kg) AUC(mg/h/l) MRT(h) MAT(h) CIVF(l/h/kg) F (%) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 6.43 Abbrevatons. k a : Absorpton rate constant (frst order). A Largest (fastest) dsposton ( = hybrd) rate constant. X z : Smallest (slowest) dsposton ( = hybrd) rate constant. fj a : Absorpton half-tme. t{x\: The dsposton half-lfe assocated wth the ntal slope (A) of a sem-logarthmc concentratontme curve, r^: The elmnaton half-lfe assocated wth the tennnal slope (A«) of a semlogarthmc concentraton-tme curve, w: The tme to reach peak or maxmum concentraton followng drug admnstraton. C m : peak or maxmum concentraton followng extravascular admnstraton. V z : the apparent volume of dstrbuton calculated by the area method. V a : the apparent volume of dstrbuton at steady state. AUC: the area under the plasma concentraton-tme curve from zero to nfnty. MRT: mean resdence tme. MAT: mean absorpton tme. CL/F: the total body clearance of drug from the plasma. F: boavalablty.

7 648 C. M. CÁRCELES ETAL. Table 2. Pharmacoknetc parameters (mean ± SD) descrbng the dsposton of amoxcttn and clavulanc acd after ntravenous or ntramuscular admnstraton n chckens (25 mg/kg, 20 mg/kg of amoxcïlln and 5 mg/kg of clavulanc acd) Intravenous route (w= 10) Intramuscular route (n = 5) Parameters Amoxclln Clavulanc Amoxclln Clavulanc.(h" 1 ) A, (h" 1 ) ha (h) tx (h) C max (mg/1) F K (I/kg) AUC (mg/h/1) 2VlRT(h) MAT(h) CUF (1/h/kg) F (%) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±5.85 admnstraton (P< 0.05), but there were no sgnfcant dfferences n total body clearances (Cl/F). Wthn each speces, boavalablty (F) for both drug substances was smlar after the ntramuscular admnstraton (P>0.05) but a sgnfcantly hgher value (P<0.05) was found n chckens than turkeys. After ntramuscular admnstraton, the parameters AUC and peak plasma concentraton (C max ) 3 whch are dose-dependent, dffered (P<0.05) between amoxclln and clavulanc acd data, but the tme taken to reach peak concentraton (tmnd, whch s not dose-dependent, dd not dffer sgnfcantly (P>0.05) between the speces. DISCUSSION The effectveness of an antmcrobal agent n treatng bacteral nfectons s dependent upon ts ablty to penetrate the nfected ste. If the antbotc s to be admnstered as one component of a combnaton, such as amoxclln wth the /Mactamase nhbtor clavulanc acd, t s partcularly mportant that the nhbtor should penetrate wth a smlar effcency to the antbacteral component (Woodnutt et al., 1990). For ths reason, t s very mportant to ncrease basc pharmacoknetc knowledge n order to predct the dosage regmens and thereby optmze the therapeutc effect of the drug (Dorresten, 1991). Usng Akake's nformaton crteron (Yamaoka et al., 1978) the amoxclln and clavulanc acd plasma concentraton v. tme data after ntravenous admnstraton of the combnaton preparaton were best ftted to a two-compartment open

8 KINETICS OF AMOXICILLIN/CLAVULANATE IN BIRDS 649 model n both speces. Ths concluson s n agreement wth that found n prevous studes carred out n varous anmal speces (Mzen et al., 1981; Bolton et al., 1984; Senor et al., 1985; Dorresten et ah, 1987). After ntramuscular admnstraton the data of both drug substances ftted an open one compartment model wth frst order absorpton n turkeys and chckens. A smlar result wth amoxclln was reported by Dorresten et al. (1987) n the pgeon. Perhaps the most mportant parameter s the mean half-lfe of the termnal phase fab) or half-lfe of the drug. No sgnfcant dfferences between turkeys and chckens were found n the half-lfe of amoxclln, but the half-lfe of clavulanc acd n turkeys was sgnfcantly longer (P<0.05) than n chckens after ntravenous admnstraton. No sgnfcant dfferences were found n amoxclln and clavulanc acd half-lves wthn each speces. For brds only a few pharmacoknetc data on /Mactams have been publshed. Dorresten et al. (1987) reported n the pgeon a shorter mean half-lfe of amoxclln after ntravenous (0.76 ± 0.16 h) and ntramuscular (0.55 ±0.11 h) admnstraton than we have found n the chcken and turkey. Mean resdence tme (MRT) s the statstcal moment analogy to half-lfe. After ntravenous admnstraton n both speces MRT reflects the smlartes wth amoxclln and the dfferences wth clavulanc acd n persstence n the body. It also reflects the longer half-lfe of amoxclln and clavulanc acd after ntramuscular admnstraton compared to the ntravenous treatment n both speces, whch s the opposte to the results reported n pgeons (Dorresten et a, 1987). The body clearances after ntravenous admnstraton of amoxclln and clavulanc acd n turkeys were sgnfcantly (P<0.05) slower than n chckens. The dfference n rate of excreton of clavulanc acd reflected n the clearance values may be due to dfferences n the elmnaton half-lfe (j^) of the drug, but ths was not the case wth amoxclln. The body clearances of amoxclln n both speces were found to be slower than that reported by Dorresten et al. (1987) n pgeons, and somewhat faster than that found n some mammals (Cragmll et al., 1992; Montesssa et al., 1988). The values for the knetc terms descrbng the dsposton of clavulanate ndcated that the drug had a sgnfcantly more rapd, but lmted dstrbuton and was more rapdly elmnated n chckens than n turkeys. The apparent volume of dstrbuton (F calculated by the area method) s the volume of flud whch would be requred to contan the amount of drug n the body f t were dstrbuted at a drug concentraton equal to that n the blood (1 I/kg). A V z value > 1 I/kg means that concentratons n other compartments wll be hgher than n the extracellular flud, except when the plasma proten bndng s hgh. For both antbotcs and routes of admnstraton, no sgnfcant dfferences (P>0.05) between turkeys and chckens were found n V z, but these volumes were sgnfcantly (P< 0.05) hgher for amoxclln than for clavulanc acd n both speces, showng a greater dstrbuton for amoxclln. For both antbotcs and speces, hgher values (P< 0.05) of V z were found after ntramuscular admnstraton due to the absorpton phase nfluence. In pgeons, Dorresten et al. (1987) obtaned smlar V z values for amoxclln after ntravenous (1.514 I/kg) and

9 650 C. M. CÁRCELES ETAL. ntramuscular admnstraton (1.555 l/kg). Boavalablty (F) s smlar n both drugs and speces and hgher than that for amoxclln n pgeons (Dorresten et al, 1987). Based on data reported before (Whte et al, 1983; Focht et al, 1984; Slocombe et al, 1984), the mnmum nhbtory concentraton (MIC) of amoxclln/clavulanc acd combnaton for senstve mcro-organsms, ncludng all the mportant Gram-postve and many Gram-negatve bactera s less than 0.5 mg/1 (expressed as concentraton of amoxclln). Accordng to plasma concentratons acheved n the normal turkey and chcken n ths study, and dosage calculatons based on the parameters descrbng dsposton (Baggot, 1977), ntramuscular dosage regmens can be recommended for the treatment of nfectons caused by susceptble organsms (MIC 0.5 and mg/1). For turkeys 75 or 18 mg/kg of the amoxclln/clavulanc acd (4:1) combnaton can be admnstered every 8 hours to acheve plasma concentratons over 0.5 or mg/1, respectvely. For chckens, 105 or 25 mg/kg of the combnaton can be admnstered every 8 hours to reach plasma concentratons over 0.5 or mg/1, respectvely. Doses öf 125 mg/kg of the combnaton can also be admnstered n turkeys every 12 h attanng plasma concentratons over mg/1. However, ths dosage regme may result n fluctuatons whch could lead to a low effectveness of the treatment or to an overdose wth sde-effects although Cooper (1985) found that 125 mg/kg of clavulanate-potentated amoxclln admnstered orally for 7 days to pgeons gave no adverse reactons. REFERENCES ALAMAN, C. (1991). Amoxclna-Acdo clavulánco, una asocacón nnovadora en la terapéutca de los procesos respratoros del ganado vacuno. Medcna Veternara, 11, ARONSON, J.K., DENGLER, H.J., DETTLI, L. & FOLLATH, F. (1988). Standardzaton of symbols n clncal pharmacology. European Journal of Clncal Pharmacology, 35, 1-7. BAGGOT, J.D. (1977). Prncples of Drug Dsposton n Domestc Anmas (Phladelpha, W.B. Saunders Company). BOLTON, G.C., ALLEN, G.D., FILER, C.W. & JEFFERY, D.J. (1984). Absorpton, metabolsm and excreton studes on clavulanc acd n the rat and the dog. Xenobotca, 14, BYWATER, R.J., PALMER, G.H., BUSWELL, J.F. & STANTON, A. (1985). Clavulanate-potentated amoxyclln: actvty n vtro and boavalablty n the dog. The Veternary Record, 12, COOPER, J.E. (1985). Safety and effcacy of clavulanate-potentated amoxyclln n pgeons (Columba lva). Research n Veternary Scence, 39, CRAIGMILL, A.L., PASS, M.A. & WETZLICH, S. (1992). Comparatve pharmacoknetcs of amoxclln ntravenously to sheep and goats. Journal of Veternary Pharmacology and Therapeutcs, 15, DORRESTEIN, G.M. (1991). The pharmacoknetcs of avan therapeutcs. Veternary Clncs of North Amerca: Small Anmal Practce, 6, DORRESTEIN, G.M., VAN GOGH, H. & RINZEMA, J.D. (1984) Pharmacoknetc aspects of pencllns, amnoglycosdes and chloramphencol n brds compared to mammals. A revew. The Veternary Quarterly, 6, DORRESTEIN, G.M., VAN GOGH, H., RINZEMA, J.D. & ButTELAAR, M.N. (1987). Comparatve study of ampclln and amoxyclln after ntravenous, ntramuscular and oral admnstraton n homng pgeons (Columba lvd). Research n Veternary Scence, 42, FOCHT, J., KLIETMANN, W. & HEILMANN, H.D. (1984) In vtro actvty of Augmentn aganst clncally mportant Gram-postve and Gram-negatve bactera n comparson wth other antbotcs. Zentralblatt fur Bakterologe, Mkrobologe und Hygene A, 256,

10 KINETICS OF AMOXICILIJN/CLAVULANATE IN BIRDS 651 FOULSTONE, M. & READING, C. (1982). Assay of amoxyclln and clavulanc acd, the components of Augmentn, n bologcal fluds wth hgh-performance lqud chromatography. Antmcrobal Agents and Chemotherapy, 22, MIZEN, L., BHANDAIR, K., SAYER, J. & CATHERRALL, E. (1981). Pharmacoknetcs and dstrbuton of Augmentn (amoxyclln and clavulanc acd) n laboratory anmals. Drugs under Expermental and Clncal Research, 7, MONTESISSA, C., CARLI, S., SONZOGNI, O., GARLAPPI, R. & SERICOLA, A. (1988). Pharmacoknetcs of sodum amoxyclln n horses. Research n Veternary Scence, 44, POWERS, J. (1990). Statstcal analyss of pharmacoknetc data. Journal of Veternary Pharmacology and Therapeutcs, 13, SENIOR, D.F., GASKIN, J.M., BUERGELT, C.D., FRANKS, P.P. & KEEFE, T.J. (1985). Amoxyclln and clavulanc acd combnaton n the treatment of expermentally nduced bacteral cystts n cats. Research n Veternary Scence, 39, SLOCOMBE, R., BEALE, A.S., BOON, R.J., GRIFFIN, K.E., MASTERS, P.J., SUTHERLAND, R. & WHITE, A.R, (1984) Antbacteral actvty n vtro and n vvo of amoxyclln n the presence of clavulanc acd. In: POSTGRADUATE MEDICINE: CUSTOM COMMUNICATIONS (Eds), Progress and perspectves on betalactamase nhbton: A revew of Augmentn, pp (New York). WHITE, A.R., BOON, R.J., MASTERS, P.J. & SUTHERLAND, R. (1983) Antbacteral actvty of amoxyclln/ clavulanc acd (Augmentn) n vtro, In: E.A.P. CROYDON & M.F. MICHELE (Eds): Augmentn: Clavulanate-potentated amoxyclln, pp (Amsterdam, Excerpta Medca). WOODNUTT, G., BERRY, V., KERNUTT, I. & MIZEN, L. (1990). Penetraton of amoxyclln, tcarclln and clavulanc acd nto lymph after ntravenous nfuson n rabbts to smulate human serum pharmacoknetcs. Journal of Antmcrobal Chemotherapy, 26, YAMAOKA, K., NAKAGAWA, T. & UNO, T. (1978). Applcaton of Akake's Informaton Crteron (AIC) n the evaluaton of lnear pharmacoknetc equatons. Journal of Pharmacoknetcs and Bopharmaceutcs, 6, RESUME Pharmacocnétque de l'assocaton amoxcllne/acde clavulanque après admnstraton ntraveneuse et ntramusculare chez le dndon et le poulet Les aspects pharmacocnétques de l'assocaton amoxcllne/acde clavulanque (4:1) ont été étudés après admnstraton ntraveneuse et ntramusculare de doses unques (25mg/kg de pods vf) à 15 dndons et 15 poulets. L'objectf état de détermner s'l exstat des dfférences entre les dndons et les poulets concernant la cnétque de dsponblté des deux produts. Les concentratons plasmatques ont été analysées par les méthodes de pharmacocnétque compartmentale et non compartmentale. Les courbes de dsponblté pour les deux substances après admnstraton ntraveneuse ont été meux nterprétées chez le dndon et le poulet par le modèle ouvert à deux compartments. Les volumes apparents de dstrbuton de l'amoxcllne et de l'acde clavulanque ont été comparables dans les deux espèces mas la clearance corporelle a été sgnfcatvement plus fable chez le dndon que chez le poulet. La dem-ve d'élmnaton de l'amoxcllne a été comparable chez le dndon (1,12 ±0,09 h) et le poulet (1,03 ±0,11 h) après njecton ntraveneuse mas celle de l'acde clavulanque dfférat sgnfcatvement (P<0,5) entre le dndon (l,12±0,03h) et le poulet (0,98 ±0,05 h). Après njecton ntramusculare les deux produts avaent une dem-ve sgnfcatvement plus longue (P<0,05) chez le dndon et le poulet que lors d'njecton ntraveneuse. La bodsponblté après tratement ntramusculare a été élevée et semblable avec les deux médcaments mas des valeurs plus grandes ont été obtenues chez le poulet comparé au dndon.

11 652 C. M. CÁRCELES ETAL. ZUSAMMENFASSUNG Pharmakoknetk ener Kombnaton von Amoxclln und Clavulansäure nach ntravenöser und ntramuskulärer Verabrechung an Puten und Hühner Das pharmakoknetsche Verhalten ener Amoxclln/Clavulansäure (4:1)-Kombnaton wurde nach ntravenöser und ntramuskulärer Verabrechung von Enzeldosen (25 mg/kg Körpergewcht) an 15 Puten und 15 Hühnern untersucht. Dabe sollte festgestellt werden, ob es zwschen Puten und Hühnern hnschtlch der Vertelungsknetk von Amoxclln und Clavulansäure Unterschede gbt. De Daten der zetabhänggen Plasmakonzentratonen wurden mt pharmakoknetschen Kompartmentmethoden und Ncht-Kompartmentmethoden analysert. De Vertelungskurven beder Medkamente nach ntravenöser Verabrechung wurden be Puten und Hühnern am besten durch en offenes Zwekompartmentmodell dargestellt. De apparenten Vertelungsvolumna von Amoxclln und Clavulansäure waren be beden Spezes annähernd glech. De Körperclearance von Amoxclln und Clavulansäure war be Puten sgnfkant langsamer als be Hühnern. De Elmnatonshalbwertzet von Amoxclln nach ntravenöser Verabrechung war be Puten (1,12 ±0,09 h) und Hühnern (1,03 ±0,11 h) annähernd glech lang, aber de der Clavulansäure dffererte sgnfkant (P< 0,05) zwschen Puten (1,12 ±0,03 h) und Hühnern (0,98 ±0,05 h). Nach ntramuskulärer Verabrechung hatten bede Medkamente n Puten und Hühnern ene sgnfkant längere Halbwertzet (P<0,05) als nach ntravenöser Behandlung. De Boverfügbarket nach der ntramuskulären Injekton war hoch und be beden Medkamenten annähernd glech, aber be Hühnern wurden höhere Werte errecht als be Puten. RESUMEN Farmacocnétca de la combnacón ácdo clavulánco-amoxclna tras la nyeccón ntramuscular e ntravenosa en pavos y gallnas Se estudó el comportamento farmacocnétco de la combnacón ácdo clavulánco-amoxclna tras la noculacón ntravenosa e ntrasmuscular de una sola doss (25 mg/kg peso corporal) a 15 pavos y 15 gallnas. El objetvo de dcho expermento fue determnar s exstían dferencas entre los pavos y pollos en la cnétca de estas dos sustancas. Se estudó los datos de tempo-concentracones plasmátcas medante farmacocnétca compartmelzada y no compartmelzada. La curvas de dsposcón para ambos fármacos tras la admnstracón ntravenosa fueron descrtas de mejor modo empleando el modelo aberto de dos compartmentos en ambas especes. Los volúmenes aparentes de dstrbucón de la amoxclna y del ácdo clavulónco en los pavos fueron smlar en ambas especes. La elmnacón corporal de amoxclna y ácdo clavulónco en los pavos fue sgnfcatvamente nferores a los de las gallnas. La vda meda de la amoxclna fue smlar en pavos (1.12 ± 0.09 h) y en las gallnas (1.03 ±0.11 h) tras la admnstracón ntravenosa pero la del ácdo clavulónco dfró sgnfcatvamente (P<0.5) entre los pavos (1.12 ± 0.03 h) y los pollos (0.98 ± 0.05 h). Por el contraro, la admnstracón de ambos fármacos por vía ntramuscular tuvo una vda meda sgnfcatvamente más elevada (P<0.05) en pavos que en gallnas al compararlo con el tratamento ntravenoso. La bodsponbldad de ambos fármacos tras su nyeccón ntramuscular fue elevada y smlar pero los valores más elevados se obtuveron en los pollos.