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Pharmacokinetics, renalclearance and metabolismof ciprofloxacin followingintravenous and oraladministration to calves and pigsJ. F. M. Nouws a , D. J. Mevius b , T. B. Vree c , A. M.Baars c & J. Laurensen aa R.V.V.‐District 6, PO Box 40010, Nijmegen, 6504 AA,The Netherlandsb Department for Large Animal Medicine, Faculty ofVeterinary Medicine, Utrecht, The Netherlandsc Clinical Pharmacy, St. Radboudhospital, Nijmegen, TheNetherlandsPublished online: 01 Nov 2011.

To cite this article: J. F. M. Nouws , D. J. Mevius , T. B. Vree , A. M. Baars & J. Laurensen(1988) Pharmacokinetics, renal clearance and metabolism of ciprofloxacin followingintravenous and oral administration to calves and pigs, Veterinary Quarterly, 10:3,156-163, DOI: 10.1080/01652176.1988.9694165

To link to this article: http://dx.doi.org/10.1080/01652176.1988.9694165

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Pharmacokinetics, renal clearance andmetabolism of ciprofloxacin followingintravenous and oral administration tocalves and pigs

J. F. M. Nouws1, D. J. Mevius2, T. B. Vree3, A. M. Baars3and J. Laurenseni

SUMMARY The pharmacokinetics of ciprofloxacin, a quinoline derivative with markedbactericidal activity against gram-negative bacteria, was studied in calves and pigs followingintravenous and oral administration.Ciprofloxacin was rapidly and well distributed in the body, exhibited a short elimination half-life of 2.5 h in both species, and was rapidly absorbed after oral administration (Tnax:2 to3 h). The oral bioavailability in calves was 53 ± 14% and for 1 pig 37.3%.The renal clearance of the unbound ciprofloxacin for both species was of the same order,indicated a predominantly tubular secretion pattern, and accounted for about 46% of the totaldrug elimination. No complete drug mass balance could be demonstrated. Small amounts oftwo metabolites were detected in the urine of calves, but not in pig urine.

INTRODUCTION

In the last 5 years flumequine, a 'second generation' quinoline, has been usedsuccessfully in veterinary medicine in the treatment of gastrointestinal infections(caused for instance by Salmonella spp and E.coli) in the calf, pig and poultryindustry without an obvious increase in flumequine resistance (4, 8, 15, 20).Recently, a so-called 'third generation' fluoroquinolone derivative, ciprofloxacin(Bay 0 9867), has been introduced into human medicine; this compound possessesa superior in vitro antibacterial activity in comparison to flumequine (Table 1)and to older, related compounds, such as nalidixic, pipemidic, and oxolinic acidsand norfloxacin; also mycoplasmacidal and rickettsiacidal activity has beenreported (4, 9, 10, 17, 19, 20). Its bactericidal activity is not fully elucidated, butits mechanism of activity is based mainly on inhibition of DNA gyrase, an essentialbacterial enzyme, that maintains, among others, the superhelical twists in DNA.Because of its breadth and intensity of activity against gram-negative pathogensand the fact that no cross-resistance with beta-lactams or aminoglycosides occurs,ciprofloxacin may also be of considerable clinical use in veterinary medicine (e.g.Salmonella spp. and E.coli infections). Numerouspharmacokinetic and favourableclinical reports from human medicine are available (5, 9, 14, 16, 17, 18), but studies

-in food-producing animals are scarce (19).The purpose of the present study was to describe the pharmacokinetics, plasmaprotein binding, urinary recovery, renal clearance, and metabolism of ciproflox-acin following intravenous and oral administration tot calves and pigs.

R.V.V.-District 6, PO Box 40010, 6504 AA Nijmegen. The Netherlands.2 Department for Large Animal Medicine, Faculty of Veterinary Medicine, Utrecht. The Netherlands.3 Clinical Pharmacy, St. Radboudhospital, Nijmegen. The Netherlands.

156 THE VETERINARY QUARTERLY, VOL 10, No. 3, JULY 1988

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Table 1. In vitro antimicrobial activity of ciprofloxacin and flumequine (Ag/m1).

Organism

P. aeruginosa

Aeromonas hydrophilia

Pasteurella multocida

Klebsiella spp.

Haemophllus influenza

E.coli

Salmonella spp.

Yersinia enterocolitica" pseudotbc

Cram-positive cocci

Clostridia sPP.

Campylobacter jejuni

Vibrio spp.

Mycoplasma spp.

MIC50/MIC90 MIC50/MIC90

Ciprofloxacin Flumequine(ref.4,8,20)(ref.I7,19)

0.25/0.5 8/16

<0.01/0.01 0.1/0.5

0.01/0.06 0.4/0.8

0.06/0.25

<0.02/0.02

0.02/0.12 0.4/0.8

0.02/0.12 0.4/0.8

0.01/0.02

0.03/2

0.25/16

0.13/0.25

0.06/

0.25/1.0

0.3/0.5

MATERIAL AND METHODS

Drugs

Ciprofloxacin - 1% solution (lot no. Pt 974516) and two of its metabolites, namely BayR 3964 (MI), ring-opened derivative and Bay Q 3542 (M2), 4-oxo-ciprofloxacin), weredonated by Bayer Ltd (Leverkusen, BRD). (Fig. I).

Animals

Three preruminant male MRY calves (weight 70 - 75 kg; age 4 weeks) and four pigs (weight29 - 32 kg) were confined in metabolic cages with separate urine and faeces collectionfacilities. Ciprofloxacin was administered IV to calves at a dose rate of 2.80 ± 0.11 mg/kg, and three days later ciprofloxacin was suspended in the morning milk replacer at thesame dose rate. Three pigs received an IV injection of 3.06 ± 0.46 mg/kg and one pigwas dosed orally with 3.1 mg ciprofloxacin/kg as a drench.Heparinised blood samples were taken by vacutainer® (Becton & Dickinson Ltd) atpredetermined intervals; spontaneously voided urine was collected, the volume measuredand a sample frozen at 20° C pending analysis.

HPLC analysis

HPLC equipment as described elsewhere was used (11, 16). The column was a Spherisorb5 ODS (250x4.6 mm I.D.; Chrompack art. 28812) without a guard column; the mobile

phase was a mixture of: 150 ml of acetonitrile (Merck 3), 150 ml of N,N-dimethylformamide(Merck 3053), 1.13 g of H3PO4 (Merck 565), 0.38 g of tetramethylammoniumchloride(Merck 822156) and 700 ml distilled water. The solvent rate was 1.5 ml/min, and theanalyses were performed at 20°C. An injection loop of 100 ul was used and the detectionof ciprofloxacin and two of its metabolites was performed at 278 nm.

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COOH

ci prof loxacin

0

H2N-CH2-CH2-HN

0

M2(BAY 0 3542)

COON

M ( BAY1

R 396C )

COON'

Figure 1. Structural formula of ciprofloxacinand two of its metabolits.

Sample preparation

To 200 pl sample (plasma, urine), 200 eul of 0.067 M. phosphate buffer of pH 7.5 and 3ml of dichlormethane were added, mixed by rotation for 20 minutes, and centrifuged at4500 g; 2.4 ml of the underlayer (dichlormethane) was removed and evaporated to drynessat 40°C under a gentle stream of nitrogen. The residue was dissolved in 500 il of eluent,and 100 pl was injected into the system. This procedure was done with and without beta-glucuronidase pretreatment of the sample.

Protein binding

Ultrafiltrates were obtained as described (11) and injected directly into the HPLC systemfor determination of the free drug fraction.

Pharmacokinetic analyses

Standard procedures (1) were followed in calculation of pharmacokinetic parameters afterIV (two-compartment model) and oral (one-compartment model) administration, andrenal clearance values.

RESULTS

Figs. 2 and 3 show the mean plasma and urine concentration-time curves afterIV and oral ciprofloxacin administration to calves and pigs. Twenty-four hoursafter IV administration, the urinary drug concentrations in pigs and calves were8.9 ± 4.6 and 4.9 ± 2.1 mg/m1 respectively. Selected pharmacokinetic parametersderived from IV data are presented in Table 2. For ciprofloxacin short distribution(T1120) and elimination (TIR) half-lives were evident. The calculated Vd(area) inpiglets was significantly larger (P<0.01) than that in preruminant calves. Thedistribution rate constant into the peripheral compartment (K12) was identical incalves and piglets, but the ciprofloxacin back diffusion out of the peripheralcompartment (K21) was in calves 2 -3 times faster than in piglets.Oral ciprofloxacin administration revealed a maximum plasma drug (Cmax)concentration within 2 to 3 h (Tmax); the disposition half-life in calves wasapproximately 3 times longer than after IV administration (Table 3). Thecalculated bioavailability based on the AUC was 53.0 ± 14.0%, and based onurinary recovery 58.0 ± 17.7%.

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100 CiprofloxacinCalves; dose 2 8 mg/kg

Urinary

drug

concen-

tration

Plasma(n=3)

--o intravenous

0 10 20 30

Hours a f ter administration.

0 10 20 30

Hours alter administration.

Figure 2. Urinary and plasma disposition of Figure 3. Urinary and plasma concentration-ciprofloxacin in three calves following intraven- time profiles of ciprofloxacin in pigs followingous and oral dosage of 2.8 ± 0.11 mg/kg in a intravenous(n=3)and oral(n=l)administration.crossover trial.

Table 2. Pharmacokinetic parameters for ciprofloxacin administered intravenously to preruminantcalves and piglets (mean ± s.d.).

Calves

(1,3)Piglets

(1-3)

Dose, mg/kg 2.80 + 0.11 3.06 + 0.46

Cp, mg/m1 1.51 + 0.13 1.91 + 0.35

Ao, mg/m1 0.53 + 0.045 1.37 + 0.26

T 1/2a'

hr 0.28 + 0.04 0.42 + 0.046

Bo' pemi 0.98 + 0.15 0.54 + 0.17

T1/213' hr 2.44 + 0.61 2.57 + 0.29

AUCo_oo,hr.mg/ml 3.93 + 0.77 2.88 + 0.52

B12/g21 0.37 + 0.05 0.83 + 0.24

Vo, litre/kg 0.54 + 0.03 0.63 + 0.12

Vgoreoplitre/kg 2.50 + 0.20 3.83 + 0.78

C19, ml/min/kg 12.1 + 2.0 17.3 + 3.7

Clrpopi, ml/min/kg(*) 28.2 + 14.8 20.2 + 3.1

Clcreatini .ml/mirakE(*)ne 0.84 + 0.11 2.09 + 0.41

(*) Mean + SEM.

The plasma protein binding for ciprofloxacin in pigs was 23.6 ± 1.7 (n=9) andin calves 70.0 ± 4.2% (n=18).The renal clearance values of the free drug in piglets and calves were similar (mean± SEM: 20.2 ± 3.1 and 28.3 ± 14.8 ml/min/kg, respectively; Tables 2 and 4),

THE VETERINARY QUARTERLY, VOL. 10, No. 3, JULY 1988 159

13 1

oral,

1000

100

10

Ciprofloxacin

Pup, dose 3D5rngrirg

Urinarydrugconcen-

tration

Plasma-41 aiuguilucurroluugl

- orolls.i1

10

rot

01 P

8b

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Table 3. Pharmacokinetic parameters of ciprofloxacin following oral administration to 3 calves andI piglet.

Number Dose Tina, Tman Ceam 11/2 AUC0_ 12h Bioavailability(.)

mg/kg hr hr jug/ml hr hr.pg/m1

Calves

1 2.86 1.1 3 0.25 6.6 2.2 56.4

2 2.67 1.1 3 0.15 8.0 1.2 37.5

3 2.86 0.3 3 0.40 9.3 3.0 65.0

Mean 2.80 0.83 3 0.27 8.0 2.1 53.0s.d. 0.11 0.46 0.13 1.4 0.9 14.0

4 3.3 0.5 2 0.17 3.1 1.16

(4) Bloavailability, AUC0,..1/AUC10 (administered dosages were identical

in IV and oral experiment).

(**) The mean AUCIV value (Table 2) was used for calculation of the

bioavallability (with correction for the dose level).

being at least 10 times higher than the creatinine clearance and indicated apredominantly tubular secretion pattern of the drug. The urinary ciprofloxacinrecovery following IV administration was for calves and pigs 45.6 ± 4.7 and 47.9± 6.1% respectively. Following oral ciprofloxacin administration, the urinaryrecovery decreased to about 55% of that after IV administration (Table 4).In the urine (not in plasma) of calves there were traces of MI and M2 metabolites,which were absent in urine of piglets (detection limit: 0.01 pg/m1). No glucuronideconjugates of ciprofloxacin or of its metabolits (MI, M2) could be detected inplasma or urine of calves and piglets.

DISCUSSION

Pharmacokinetics

Ciprofloxacin exhibited favourable pharmacokinetic properties: it is rapidly andwell distributed in the body and it possesses a reasonable oral bioavailability.The renal elimination of ciprofloxacin is predominantly by tubular secretion. Theelimination half-life of ciprofloxacin, being about 2.5 h, is identical for calves,piglets and man (5, 16), and is similar to that of flumequine in calves (20). In fish(carp, catfish, trout) the elimination half-life of ciprofloxacin is 5-fold longer (12).Following oral administration of ciprofloxacin to calves, a 3-fold longer plasmadrug disposition half-life was noticed than after IV injection (Fig. 2). Anexplanation may be the slow release from the milk replacer (ciprofloxacin depot)with a subsequent prolonged absorption effect. Besides age (maturity of renalfunction and metabolic capacity of the liver), breed difference as well as feedcomposition may profoundly influence the ciprofloxacin plasma concentration-time profile. It is noteworthy that with another quinolone (Baytril,®), which isstructurally closely related to ciprofloxacin, a two-fold higher plasma drugconcentration was reported in calves of the same age given the same oral dosage(7).

Bioavailability and metabolism

The mean bioavailability data of the orally administered ciprofloxacin to calves,based on the AUC values and urinary drug recovery data of IV versus oral routeof administration, were 53.0 and 58.0%, respectively. With respect to the drug

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Table 4. Urinary recovery and renal clearance of ciprofloxacin and two of its metabolites in pigsand calves following intravenous and oral administration.

Animal Urinary drug recovery(*) Urineflow

ml/min

Renal clearance

creatinine

ml/min/kg

Renal clearancetotal

ciprofloxacinml/min/kg

Renal clearanceunboundciprofloxacinml/min/kg

Cipro- MIno. floxacin

82

X

IntravenousPig i 53.1 0.84 + 0.50 2.56 + 1.99 16.9 + II.2(n-5) 21.6 + 14.3(n-5)

Pig 2 44.9 0.36 + 0.04 1.89 + 0.46 12.6 + 4.9 (n-3) 16.7 + 6.5 tens,Pig 3 44.0 1.23 + 0.76 1.83 + 1.24 16.9 + 4.6 (n-5) 22.4 + 6.1 (n..5)

Mean 47.3 0.81 2.09 15.5 20.2SEM 5.0 0.43 0.41 2.5 3.1

Oral

Pig 4 26.2 -- 1.03 + 0.34 1.31 + 0.36 6.5 + 3.8 (n-5) 8.5 + --IntravenousCalf 1 41.8 2.4 10.2 + 8.3 0.72 + 0.32 7.0 + 5.1 (0-10)** 22.4 + 16.4(n10)**

Calf 2 50.8 1.7 2.2 13.3 + 12.6 0.92 + 0.36 11.2 + 7.0 (n-.10)** 45.3 + 28.2(,10)**

Calf 3 44.2 1.2 4.2 + 1.8 0.88 + 0.15 4.9 + 2.0 (n-5) 17.3 + 7.2 (n..5)

Mean 45.6 1.8 9.2 0.84 7.7 28.3SEM 4.7 0.6 4.6 0.11 3.2 14.8

Oral

Calf 1 23.2 1.9 7.9 + 4.1 0.80 + 0.16 4.1 + 1.3 (0.10)** 15.5 + 4.7 (n.10)**

Calf 2 20.8 1.5 0.14 9.8 + 7.7 0.96 + 0.26 7.3 + 2.1 (011)** 20.3 + 5.9 (n11)**

Calf 3 33.1 1.5 4.6 + 2.1 0.83 + 0.39 3.3 + 0.5 (n-5) 10.0 + 1.5 (11.5)

Mean 25.7 1.6 7.4 0.86 4.9 15.2SEM 6.5 0.23 2.1 0.09 2.1 5.0

MI and M2 viz. Fig.l.* Expressed as percentage of the dose applied.** Significantly related to urine flow (P<0.05).n - number of urine samples

mass balance in pigs and calves, about 53% of the intravenously administereddose and about 74% of the orally administered dose were 'missing' in both species.In man a lesser percentage was missing; urinary drug recovery accounted for about60% of the IV administered dose (5). Although the biliary route seems to beminimal (approximately 1% of the administered dose), a considerable amountwill be excreted by the gut (3, 9) and will contribute to the observed loss in thedrug mass balance.An alternative explanation for the 'loss' of ciprofloxacin may be an extensivemetabolism of the drug. The piperazinyl ring seems to be the centre of metabolism;the ring may become oxidised (M2), opened (MI), formylated or sulphated. However,MI and M2 were minor metabolites in calves: urinary recovery was less than 2%,which is similar to man (13), and these metabolites were absent in pigs. Followingoral ciprofloxacin administration to calves and man, the MI and M2 metabolitesbecame proportionally more important (Table 4; ref. 9). Presumably other, moreimportant, metabolic pathway(s) for ciprofloxacin in calves and pigs may bepresent, or extensive degradation/conversion of ciprofloxacin may occur in thegastrointestinal tract. In this context, age and feeding are of importance in theextent of metabolism, bioavailability and drug biodegradation in the gastrointes-tinal tract following oral ciprofloxacin administration.

Protein binding

The binding of ciprofloxacin to calves plasma protein (about 70%) is similar tothat reported for flumequine (20). The difference in protein binding for ciproflox-acin between pigs (mean 23%) and calves (mean 70%) could not be explained.

THE VETERINARY QUARTERLY, VOL. 10, No. 3, JULY 1988 161

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The difference is presumably an artifact (interference of fatty acids in the drugbinding by albumin) or there is a difference between calves and pigs in availablespecific albumin and alpharacid glycoprotein binding sites (2).Therapeutic aspectsAs shown in Table 1, ciprofloxacin exhibits an impressive killing effect in vitro(even in the stationary growth phase) on bacterial pathogens of the gastrointestinaland respiratory tracts (e.g. salmonellae, E. coli spp, Pasteurella spp), and virtuallyall urinary bacterial pathogens including Pseudomonas spp. With respect toSalmonella spp. and E.coli it must be noted that the antimicrobial potency ofciprofloxacin is at least 7 times better than flumequine. Ciprofloxacin and anotherquinolone (Baytril®) possesses a similar antimicrobial spectrum (6, 7). With theIV dosage in our study (mean for pigs 3.06 mg/kg and for calves 2.80 mg/kg),plasma and tissue concentration above MIC for general pathogens (MIC > 0.12

g/m1), e.g. E.coli, Salmonella, Pasteurella spp may be anticipated for about only8h. Multiple dosing (especially in gastrointestinal diseases) is advisable for cureof the disease and for prevention of relapses, as demonstrated for Baytril® (6).The main target for ciprofloxacin is the bacterial gyrase, which reveals inhibitionof the resealing the bacterial DNA. This action may be antagonised bytetracyclines, chloramphenicol and rifampicin (14, 17, 18).In conclusion, ciprofloxacin exhibits rapid oral absorption and reasonable oralbioavailability, but its metabolism is still not elucidated. Ciprofloxacin is widelydistributed in the body and is eliminated from the body, predominantly by tubularsecretion.

REFERENCES

1. Baggot JD. Principles of drug disposition in domestic animals. W.B. Saunders Co., Philadelphia/Toronto/London, 1977.

2. Belpaire F. Species differences in protein binding. In 'Comparative Veterinary Pharmacology,Toxicology and Therapy'. Ed. Miert ASJPAM van, Bogaert MG and DeBackere M. MTP PressLtd, Lancaster 1986; 187-95.

3. Brumfitt W, Franklin I, Grady D, Hamilton-Miller JMT and Iliffe, A. Changes in thepharmacokinetics of ciprofloxacin and fecal flora during administration of a 7-day course tohuman volunteers. Antimicrob. Agents Chemother 1984; 26: 757-61.

4. Dorrestein GM, Gogh H van, Buitelaar MN and Nouws JFM. Clinical pharmacology andpharmacokinefics of flumequine after intravenous, intramuscular and oral administration inpigeons Columba livia. J Vet Pharmacol Therap 1983; 6: 281-92.

5. Drusano GL, Standiford HC, Plaisance K, Forest A, Leslie J and Caldwell J. Absolute oralbioavailability of ciprofloxacin. Antimicrob. Agents Chemother 1986; 30: 444-6.

6. Fischer W, Amtsberg G and Sindern P. Untersuchungen zur therapeutischen Wirksamkeit desChinolon-Carbonsaurederivates BAY VP 2674 (Baytri18) bei der experimentellen E. coli-Infektiondes Kalbes. Proceedings Fourteenth World Congress on Diseases of Cattle. Dublin 1986; 393-7.

7. Fischer W and Kammermeier J. Pharmacokinetische Untersuchungen tiber die Resorption vonBAY VP 2674 (Baytrile) nach oraler Applikation beim Kalb. Proceedings Fourteenth WorldCongress on Diseases of Cattle. Dublin 1986; 1174-8.

8. Goren C, De Jong WA and Doornebal P. Pharmacokinetical aspects of flumequine andtherapeutic efficacy in Escherichia coli infection in poultry. Avian Pathology 1982; 11: 463-74.

9. Hooper DC and Wolfson JS. The fluoroquinolones: pharmacology, clinical uses, and toxicitiesin humans. Antimicrob. Agents Chemother 1985; 28: 716-21.

10. LeBel M, Vallée F and Bergeron MG. Tissue penetration of ciprofloxacin after single and multipledoses. Antimicrob. Agents Chemother 1986; 29: 501-5.

11. Nouws JFM, Vree TB, Breukink HJ, Baakman M, Driessens F and Smulders A. Dose dependentdisposition of sulphadimidine and its N4-acetyl and hydroxy metabolites in plasma and milk ofdairy cows. The Veterinary Quarterly 1985; 7: 177-86.

12. Nouws JFM, Grondel JL, Schutte AR and Laurensen J. Pharmacokinetics of ciprofloxacin incarp, African catfish and rainbow trout. The Veterinary Quarterly 1988; 10: 211-6.

13. Saene JJM, Saene HKF, Geitz JN, Tarko-Smit NJPh and Lerk CF. Quinolones and colonizationresistance in human volunteers. Pharmaceut Weekbl Sci Ed 1986; 8: 67-71.

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14. Simberkoff MS and Rahal JJ. Bactericidal activity of ciprofloxacin against amikacin- andcefotaxime-resistant gram-negative bacilli and methicillin-resistant Staphylococci. Antimicrob.Agents Chemother 1986; 29: 1098-1100.

15. Theys H, Verhess I, Van de Water J, Grimon A, Meyers R and Bynens M. Antibiotic sensitivityof Salmonella strains, isolated from veal calves during the period 1982-1984. Vlaams DiergeneeskdTijdschr 1985; 5: 382-4.

16. Vree TB, Wijnands WJA, Guelen PJM, Baars AM and Hekster Y. Pharmacokinetics: metabolismand renal excretion of quinolones in man. Pharmac Weekbl Sci Ed 1986; 8: 29-34.

17. Wolfson JS and Hooper DC. The fluoroquinolones: Structures, mechanisms of action andresistance, and spectra of activity in vitro. Antimicrob. Agents Chemother 1985; 28: 581-6.

18. Zeiler HJ. Evaluation of the in vitro bactericidal action of ciprofloxacin on cells of Escherichiacoli in the logarithmic and stationary phases of growth. Antimicrob. Agents Chemother 1985;28: 524-7.

19. Ziv G and Soback S. Comparative clinical pharmacokinetics of several antibacterial quinolonesin preruminant calves. Abstracts EAVPT congress, Ghent, Belgium 1986; p 126.

20. Ziv G, Soback S, Bor A and Kurtz B. Clinical pharmacokinetics of flumequine in calves. J VetPharmacol Therap 1986; 9: 171-82.

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tion of Tables and Figures should be indicatedon the manuscript. The paper should commencewith an abstract of no more than 150 words. Theauthors should provide a number (3 to 5) of keywords and a short running title.SI units should be used.References in the text should be indicated by fig-ures (in brackets) corresponding exactly with thebibliography at the end of each paper (thisjournal prefers alphabetical order). Please statethe following particulars: (1) name and initials ofauthor(s), (2) title of paper, (3) name of journal,year of issue, volume, and opening/last page.Where books are concerned also state residenceand name of publisher.The text of the paper should be arranged intosections. In general please follow the lay out andstyle of recent numbers of this journal. Completeinstructions (and full text of the 'Vancouverstyle') for authors can be obtained from theeditorial office on request.

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