Plasma levels of oxytetracycline, doxycycline, and minocycline in pigs after oral administration in feed

A. Pijpers, E. J. Schoevers, N. Haagsma and J. H. Verheijdenadministration in feed

Plasma levels of oxytetracycline, doxycycline, and minocycline in pigs after oral

1991, 69:4512-4522.J ANIM SCI

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PLASMA LEVELS OF OXYTETRACYCLINE, DOXYCYCLINE, AND MINOCYCLINE IN PIGS AFTER ORAL

ADMINISTRATION IN FEED'

A. Pijpers2, E. J. Schoevers2, N. Haagsma3 and J.H.M. Verheijden2

State University of Utrecht, 3508 TD Utrecht, The Netherlands

ABSTRACT

Steady-state plasma levels were determined for oxytetracycline (OTC), doxycycline @C), and minocycline (MC) after medication with different in-feed concentrations. Each concentration of the three tetracyclines was examined in six pigs. The animals were housed in individual pens and fed twice daily with an interval of 12 h. All pigs consumed their feed within 1 h after it was provided. Concentrations of 400, 800, 1,600, and 2,400 mg of OTC per kilogram of feed induced steady-state plasma levels ranging from .13 to .22, .19 to SO, .39 to 1.43, and 1.41 to 2.14 pg/ml, respectively. On a feed intake basis, pigs received 13, 26, 54 to 81, and 108 mg of OTC per kilogram of BW per day, respectively. Steady-state plasma levels after medication with 200, 400, and 800 mg of DC or MC per kilogram of feed ranged from .37 to .89, .71 to 1.14, and 1.62 to 3.18 pdml for DC and from .21 to .60, .43 to 1.05, and 1.19 to 2.62 pg/ml for MC. Pigs consumed 7, 13, and 26 mg of DC and 9, 18, and 36 mg of MC per kilogram of BW per day, respectively. For all three tetracyclines there was an increase in steady-state plasma levels when concentrations in feed or per kilogram of BW increased. Plasma levels were determined with both a HPLC method and a microbiological method. A good correlation existed between the results obtained by both methods. It was concluded that based on plasma levels and known in vitro activity DC and MC could be good alternatives for OTC to treat respiratory tract infections in pigs. Key Words: Oxytetracycline, Doxycycline, Minocycline, Feed Additives, Pigs

J. Anim. Sci. 1991. 69:451%l522

introduction are often used instead of the older tetracy- Tetracyclines have been available for hu-

man and veterinary medical use for more than 40 yr. In the swine industry, tetracyclines have been applied particularly for respiratory tract infections (Kunesch, 1986). Oxytetracycline (OTC) is the commonly used compound in swine practice, usually administered orally.

In humans the newer tetracyclines, minocycline (MC) and especially doxycycline @C),

'The authors thank J ~ I I B W ~ C I S , an van ~ o u r i k , Peter van Hoeve, and Paul van Gasselt for technical assistance. This work was partially supported by the Velerinary Public Health Inspectorate, Ministry of Welfare, Public Health and Culture, The Netherlands.

'Dept. of Herd Health aad Reprod. b p i . of he Sci. of FOO~ of ~nim. origin. Received June 14, 1990. Accepted M a y 20, 1991.

clines. Doxycycline and MC are. characte& by a better lipid solubility, an improved antimicrobial activity, and a different pharmacokinetic profile (Barza et al., 1975; Aron- son, 1980).

In a previous study, we compared the in vitro activity of the tetracyclines against four porcine respiratory tract pathogens (Pijpers et al., 1989). In general, MC and DC showed the highest in vitro activity, and MC showed no crossresistance! with the other tetracyclines against Pasteurella multocidu and Actinobacil- lus pleuropneumoniae. In pigs, data about the pharmacokinetic profile of DC and MC after oral administration proved not to be available. In contrast, several studies have been pub- lished about the pharmacokinetics of OTC in pigs (Mercer et al., 1978; Black and Gentry, 1984; Mevius et al., 1986; Hall et al., 1989; Pijpers et al., 1991). Moreover, after medica-

4512



https://www.researchgate.net/publication/264715985_Drug_residues_in_food_animals_II_Plasma_and_tissue_kinetics_of_oxytetracydine_in_young_cross-bred_swine?el=1_x_8&enrichId=rgreq-5202d496-7b75-4bc3-b630-0d85a9ba8c47&enrichSource=Y292ZXJQYWdlOzIxNDAyNjE2O0FTOjEwMzM2MzAzNTI3MTE4N0AxNDAxNjU1MDc3MDA0

FEED MEDICATION WITH TETRACYCIJIWS IN PIGS 4513

tion with 400 and 550 mg of OTC per kilogram of feed, plasma concentrations ranging from .14 to .40 pglml were noted (Mevius et al., 1986; Hall et al., 1989). Recently, Kniffen et al. (1989) reported that tetracycline plasma concentrations remained constant at .4 pdml after medication with 550 m& of feed. For chlortetncycline, Kilroy et al. (1990) determined mean plasma concentrations of approximately .8 pdml after feed medication with 1.000 m a g .

The aim of the present study was to determine plasma concentrations of OTC, DC, and MC after oral administration of different amounts of the drugs in feed.

Materials and Methods

Animals. Clinically healthy, conventional pigs (Great Yorkshire x Dutch Landrace) from the University's breeding farm were used. In Exp. 1, 2, 3, and 4, respectively, 30 (27 to 66 kg), 18 (31 to 36 kg), 18 (27 to 33 kg), and 16 (37 to 43 kg) animals were involved The pigs were housed in individual pens in one stall of the farm. To acclimatize them to their environ- ment the pigs were placed in their pens 7 d before the start of the experiment. Rectal body temperatures were measured daily. At the beginniig of the acclimatization period of all experiments rectal body temperatures were elevated (39.5 to 40.8'C). However, 4 d later the values were within normal range and they remained at that level. During the acclimatization period the pigs were fed unmedicated, pelleted feed twice daily and they were given ad libitum access to drinking water via nipple waterers in each pen. The amount of offered feed was in agreement with standard amounts in practice (i-e., 30-kg BW: 1,100 g/d; 60-kg BW 2,000 g/d). During the experiments all pigs seemed clinically healthy and they consumed their feed within 1 h after it was provided.

Medicated Feed. A pelleted feed for pigs was manufactured commerciallqfl. For each experiment one batch of feed was prepared using a standard formula. One part was used as unmedicated feed, to the other part, OTC, DC,

' b e Eemstroom, Leusden, The Netherlands. '€'fiber, The Netherlands. h d e r l e - C anamid, The Netherlands. 7Ven0j~t@! Terumo Corp., Tokyo, Japaa

or MC was added to prepare medicated feed. Pure oxytetracycline hydrochlorides and doxycycline hydrochlorides were used, Minocy- cline was supplied as a 10% premix with glucose6. The drugs were added to the feed- base as a 1-kg premix with lactose. During pelleting, feed temperature was 58 to 61'C. After manufacturing, samples of 1 kg each were taken at random to determine the amounts of OTC, DC, and MC.

Experimental Design of Experiments I, 2 , and 3. In Exp. 1 five groups of six pigs were fed 400, 800, 1,600, 1,600, and 2,400 mg of OTC per kilogram of feed, respectively, equivalent to 13, 26, 54, 81, or 108 mg of OTC per kilogram of BW per day. In Exp. 2, three groups of six pigs were given 200, 400, and 800 mg of DC per kilogram of feed, whereas the same doses of MC in the feed were administered to three groups of six pigs in Exp. 3. On a feed consumption basis the pigs consumed 7, 13, or 26 mg of DC per kilogram of BW per day and 9, 18, or 36 mg of MC per kilogram of BW per day, respectively.

Feed was provided twice daily at 0800 and 2000 and all pigs in one group received at each time a standard amount of feed. Just before the first medicated feeding, blood samples (20 ml each) from the caval or jugular vein were drawn by puncture into heparinized vacutainer tubes7. Six days later, blood samples were drawn just before and 3 h after the 13th feeding of the pigs. Plasma samples were collected after centrifugation and then stored at -2o'c.

Experimental Design of Experiment 4. Two groups of eight pigs were fed 1,600 mg of OTC or 300 mg of DC per kilogram of feed, which corresponded with 62.2 mg of OTC and 11.5 mg of DC per kilogram of BW per day. Feed was provided twice daily at 0800 and 2000. Blood samples were collected just before the first supply of medicated feed and at 12, 24, 36, 60, 84, 108, and 132 h thereafter. Plasma samples were collected after centrifugation and then stored at -20°C.

Determination of OTC, DC, and MC in Feed. Approximately 2 g of ground feed was accurately weighed into a 20-ml stoppered centrifuge tube. The feed was extracted with 10 ml of Mcnvain's buffer (Martinez and Shimoda, 1988), pH 2.0 (.lo M citric acid: .20 M disodium hydrogen phosphate = 123:77 VOV vol; the pH was adjusted to 2 with HCl),



https://www.researchgate.net/publication/20444653_Bioavailability_pharmacokinetics_and_plasma_concentration_of_tetracycline_hydrochloride_fed_to_swine?el=1_x_8&enrichId=rgreq-5202d496-7b75-4bc3-b630-0d85a9ba8c47&enrichSource=Y292ZXJQYWdlOzIxNDAyNjE2O0FTOjEwMzM2MzAzNTI3MTE4N0AxNDAxNjU1MDc3MDA0

4514 FiJPERs ET AL.

concentration of the tetracyclines in plasma was determined by comparing the mean zones of inhibition of samples with the mean zones of inhibition produced by standards (.l to 1.0

HPU: Procedure: OTC. DC, and MC. The method used was modified from that described by de Leenheer and Nelis (1979a,b). Two milliliters of plasma was thoroughly mixed with 3 ml of a phosphate-sulfite buffer, pH 6.5 (2.4 M disodium hydrogen phosphate:4.0 M sodium sulfite = 1:l voltvol), and extracted with 5 r d of ethyl acetate using a Vortex@ mixer. After centrifugation at 3,600 x g for 10 min, the ethyl acetate layer was collected. The extraction was repeated with another 5 ml of ethyl acetate. To the combined extracts, 200 pl of a solution of .2% ( d o l ) ascorbic acid and .l% (wt/vol) cysteine-HCl in methanol was added. The extracts were evaporated to dryness at 37' using an evaporating unit and heating module. The residue was dissolved in 1.0 ml mobile phase using a Vortex mixer for 30 s. This solution was used for HF'LC analysis. The values found were corrected for recovery (value x 100hecovery).

Aliquots of the sample and standard solu- tions (50 pl) were injected on a Chromspher C-8 column9 with a guard column (10 x 2.1

(Chrompack). The tetracyclines were detected at 350 nm using a variable wavelength detector. The eluents used are described under feed analysis.

Statisticul Analysis. Statistical analysis was performed using a commercial microcomputer packagelo. correhtions were investigated between plasma concentrations determined by the HPLC method and the agar diffusion method.

Pg/ml)*

mm) packed with reversed-pha~e material

containing .001 M NazEDTA in a shaking bath for 20 min The homogenate was centrifuged at 600 x g for 15 min. The extraction p r o d u e was repeated using 10 ml of Mcllvain's buffer, pH 4.5, containing .1 M Na2EDTA. The Supernatants were combined and filtered through a folded fiter S&S8 59$. The filtrate was centrifuged at 5,200 x g for 10 min. The supernatant was used for HPLC analysis after dilution with eluent.

Aliquots of the sample and standard solu- tions (20 pl) were injected on a Chromspher C-8 columng with a guard column (10 x 2.1 mm) packed with reversed-phase material (Chrompack). Oxytetracycline and MC were detected at 350 nm and DC at 270 nm using a variable wavelength detector. The eluents were (.l M potassium nitrate, .05 M citric acid, .033 M sodium citrate), pH 3S:dimethylformamide: ethyl acetate = 85:12:3 (vol/vol/vol) for OTC and MC and .1 M citric acidacetonitrile = 60: 40 (voVv01) for DC using a flow of .5 d m i n and .8 ml/min, respectively.

Determination of OTC, DC, and MC in Plasma

Microbiological Procedure. The assay was carried out on freshly prepared agar plates (140 mm in diameter and 2 mm thiclmess) consist- ing of 6.25 g of peptone, 9.99 g of mzW4, 1.12 g of NaOH, 2.25 g of yeast extract, .75 g of glucose, and 20 g of agar in 1 Liter of distilled water (pH of the medium = 5.9). The test organism was Bacillus cereus (ATCC 9634). The inoculum preparation and mainte nance was carried out as described by Dom- bush and Abbey (1972). A quantity of about 5,000 spores/ml of agar was used and six holes (9 mm in diameter) were cut in each plate. The holes were filled with 50 pl of sample solution and(or) reference sample prepared in swine plasma. If the concentration of the tetracyclines tended to be higher than 1.0 pg/ml, the sample solution was diluted with phosphate buffer (.074 mol/liter, pH 5.9). All samples were run in triplicate on three Werent plates and the inhibition zones were measured after incubation for 18 to 24 h at 30'C. The

*scllleicha and schull, D a s a Germany. 9100 x 3 mm, ChromPacL, Ihe Netherlands. loStatistix; NEi Analytical Software, R o d e , MN.

Results

The measured concentrations of OTC, DC, and MC in the pelleted, medicated feed are shown in Table 1. Concentrations corresponded well with the amounts added during the preparation of the feed.

In Table 2 the range, and in Figures 1, 2, and 3 the mean, plasma drug concentrations in the steady state just before and 3 h after the 13th feeding of the animals in Exp. 1,2, and 3 are shown. After feeding 1,600 mg of 0°C per kilogram of feed, corresponding to a dose of 81 mg/kg of BW per day, observed steady- state plasma concentrations ranged from .75 to



FEED MEDICATION WITH TETRACYCLINES IN PIGS 4515

TABLE 1. MEAN (* SD) CONTENT OF OXYTETRACYCLLNE (OTC), DOXYCYCUNE (DC), AND MINOCYCLINE (MC) IN FEEDa

Amount added, mpJkg mgkg n

Content measured (* SD),

Exp. 1 OTC OTC OTC OTC OTC

400 800

1,600 1,600 2,400

366* 27 778 It 20

1,522 * 186 1,5U2 * 88 2,159 * 62

Exp. 2 Dc Dc DC

200 400 800

217 f 24 436 * 13 833 f 76

6 5 5

MC MC MC

200 400 800

--r- - 235 f 11 378 rt 14 802k 21

4 4 4

Exp. 4 O X 1,600 1,700 f 128 6 Dc 300 320 rf: 36 5

Dsamples were analyzed by high performance liquid chromatography.

1.43 pg/ml. After medication of 400 mg of DC or MCkg of feed, corresponding to 13 mg of DC/kg of BW per day, or 18 mg of MC/kg of BW per day, steady-state plasma levels ranged from .71 to 1.14 pdml for DC and from .43 to 1.05 pdml for MC. The plasma levels were determined both with a HPLC and a microbiological method. The recoveries of the tetracy-

clines obtained with the modified HPLC method are given in Table 3 . A good correlation existed between the results obtained by the microbiological procedure and those obtained by the HPLC method (Figure 4).

In Figures 5 and 6 the plasma concentrations of OTC and DC, sampled just before

TABLE 2. THE RANGE OF STEADY-STATE PLASMA LEVELS OF OXYTETRACYCLINE (OTC), DOXYCYCLINE @C), AND MINOCYCLINE (MC) IN PIGS (N = 6)

OF THE DRUG IN MEDICATED FeED' ADMINISTRATION

Range of plasma drug level Mean body Drug dose m c , Microbiological,

Medicated feedb. mgkg Wt, kg mg.Q-l.& P@ P t W OTC 400 66.0 12.1 .13- .22 .09-.19 OTC 800 60.5 26.4 .le .50 .14-.43 OTC 1600 58.7 54.5 .39-1.14 .36-*74 OTC 1600 27.5 81.5 .75-1.43 N A ~ OTC 2400 30.2 111.3 1.41-2.14 NA Dc 200 33.2 6.6 .37- .89 .42-.89 Dc 400 34.2 12.9 .71-1.14 .67-1.19 Dc 800 33.7 26.1 1.62-3.18 1.7S3.18 MC 200 30.3 9.2 .21- .60 .22-.44 MC 400 31.5 17.8 .4S1.05 NA MC 800 30.8 36.4 1.19-2.62 1.10-2.82

aplasna concentrations were determined by high perforjnance l q i d chromatography and a microbiological method. bDrug concentration added to the pellets. 'NA = not available, due IO contamination.



4516 PIIPERS ET AL.

tBB@

T

13 2 7 40 54 67 81 95 110

mg of OTC/ kg BW/ day given in feed

Figure 1. Mean (+SE) steady-slate plasma oxytetracycline (OTC) concentrations of pigs @g/ml) (n = 6) after administration of medicated feed. Plasma samples were collected just before (solid bars) and 3 h after feed intake (shaded bars).

feeding, of the pigs in Exp. 4 are presented. The OTC steady-state concentrations varied between .56 and .78 pg/ml. These steady-state OTC plasma levels corresponded with the results of Exp. 1. The DC steady-state plasma concentrations varied between .56 and .87 pg/ ml. For both tetracycline steady-state was achieved quickly.

Dlscusslon

In several countries OTC feed medication is widely used for the treatment of respiratory tract infections; the recommended dose is 400 g per 1,OOO kg of feed (Commodity Board for Feeding Stuffs, 1986l'; Kunesch, 1986). To evaluate a medication, clinical efficacy has to

''Commodity Board for Feeding Stuffs. 1986. Report about the use of medicated feed in the Netherlands in 1984 and 1985.

be studied in clinical trials or in suitable infection models. An alternative way to determine dose regimens is based on in vitro minimal inhibitory concentrations (MIC) combined with pharmacokinetic data. Until now, clinical efficacy studies concerning 0°C feed medication have been scarce. It seems that the recommended 400 mg of OTC per kilogram of feed is based mainly on empirical observa- tions.

In this study, low plasma OTC concentrations were achieved (5 .2 pdml) after OTC feed medication with the recommended 400 mg per kilogram of feed. Other investigators found similar results. Mevius et al. (1986) reported plasma OTC concentrations below .2 pglml in three pigs (14 to 17 kg) given ad libitum access to medicated feed containing 400 mg of OTC per kilogram of feed. Hall et al. (1989) gave three pigs (30 kg BW) 550 g of OTC per kilogram of feed. Plasma OTC levels did not exceed .4 pdml in any of the pigs.



FEED MEDICATION WlTH TETRACYCLINES IN PIGS 4517

TABLE 3. RECOVERY OF TETRACYCLINE FROM SmKED PLASMAa

~

Added, Recovery, Comund ulml % SD n OTC .1

I .o 10.0

Dc .I 1 .o 5 .O

MC .1 1 .o

10.0

57 66 72 82 73 85

100 90 95

7.9 6 2.4 6 3.7 6 5.8 5 7.8 5 2.7 4 9.4 7 7.0 7 2.7 7

aThe high performance liquid chromatography method was used. For conditions see Materials and Methods.

Apparently, OTC absorption is limited when administered in feed. Several investigators demonstrated that OTC has a poor bioavailability after oral administration in a drench to fasted pigs (Mevius et al., 1986; Limpoka, 1978; Rjpers et al., 1991). Furthermore,

Welling et al. (1977), Neuvonen (1976), and Welling and Tse (1982) reported that the absorption of tetracyclines in humans was reduced by food.

It is generally assumed that circulating levels of drugs have to be maintained above MIC of pathogenic organisms during a come of treatment or for prophylaxis (Bergan, 1978; Powers et al., 1984; Prescott and Baggot, 1988). For OTC the mean MIC-50 values for porcine bacterial respiratory tract pathogens is .5 to 1 pg/d (Shimizu et al., 1982; Pijpers et al., 1989). In the present study a dosage of 81.5 mg of OTC per kilogram of BW per day proved to achieve mean MIC values in plasma. Those OTC plasma levels were achieved with 1,600 and 2,400 mg /kg of feed concentrations. However, one group fed with 1,600 ppm of OTC did not reach the plasma level of 1 pg/ ml. Because of a different level of feed consumption, the latter group received 54.5 mg of OTC per kilogram of BW per day, whereas

7 13 20 27 34 40 47 54 mg of DC/ kg BW/ day given in feed

Figure 2. Mean (++SF!) steady-state plasma doxycycline (DC) concentrations of pigs @@d) (n = 6) after administration of medicated feed. Plasma samples were collected just before (solid bars) and 3 h after feed intake (shaded bars).



4518 PUPERS

the other group fed 1,600 mg per kilogram of feed received 81.5 mg of OTC per kilogram of BW per day. This makes it clear that drug concentrations in feed should be dependent on the feeding regimen.

For DC and MC mean MIC values for important porcine bacterial respiratory tract pathogens are .25 to .5 pg/d (Pijpers et al., 1989). In Exp. 2 a dose of 6.6 mg of DC per kilogram of BW per day as a 200 mg/kg feed medication resulted in mean plasma levels corresponding to MIC values. After 300 mg of DC per kilogram of feed (11.5 mgflrg of BW per day) minimum plasma levels in the steady state exceeded mean MIC values. Minocycline administered in a dose of 9.2 mg per kilogram of BW per day gave mean plasma levels below .5 @ml, whereas a dosage of 17.8 mg per kilogram of BW per day as a 400 mg per kilogram of feed medication resulted in plasma levels above mean MIC values. In humans DC and MC were better absorbed than tetracycline (Wood et al., 1975; Welling et al., 1977). In

ET AL.

the present study, higher plasma levels were observed after oral administration of DC and MC than after feed medication with similar doses of OTC. Hall et al. (1988) suggested that feed

medication with 1,100 mg or 5,500 mg of OTC per kilogram of feed does not increase the plasma concentration of OTC compared with 550 mg per kilogram of feed, because OTC absorption in the gut should be inversely related to the concentration in the feed. In the present study there was an increase in steady- state plasma levels when OTC, DC, and MC concentrations in feed or per kilogram of BW per day were increased. Kilroy et al. (1990) reported that plasma chlofietracycline concentrations were highly correlated with the dose of the drug consumed.

In contrast to suggestions of Mevius et al. (1986), the appetite of the animals was not diminished when high OTC feed concentrations (2,400 mg per kilogram of feed) were administered.

2.40 -

1.80 -

1.20 -

0. 9 18 27 36 45 54

mg of MC/ kg BW/ day given in feed

Figure 3. Mean (+SEI steady-state plasma minocycline (MC) concentrations of pigs @g/ml) (n = 6) after administration of medicated feed. Plasma samples were collected just before (solid bars) and 3 h after feed intake (shaded bars).



FEED MEDICATION WITH TETRACYC”ES IN PIGS 4519

Under certain conditions tetracyclines are heat-labile (Brander et al., 1982; Moats, 1988). After pelleting 8,OOO kg of feed containing 400 mg of OTC per kilogram of feed, Counotte et al. (1984) found a loss of OTC of about 10 to 15%. In this study, OTC concentrations measured in feed differed not more than 10% from the added amounts. So, 0°C losses during the process of pelleting feed, which includes steaming, were relatively small. Measured DC and MC feed concentrations corresponded with

OXY TETRACYCLINE r - 0.9420 n - 46

1 .oo - E . y

.75

3 5 0

I

6 J

U +

2 5 L m 7

/ A

A

0. ’ 0. .25 50 .75 1.00

WLC-method rrg/ml

the added amounts, taking into account mea- suring errors.

The HPLC method used is based on methods normally applied in tetracycline analysis, and the extraction solvents used are based on those described by Martinez and Shimoda (1988). No further clean-up was required before HPLC analysis. When apply- ing the HPLC system described, signals of matrix interferences were only observed at low levels. These signals did not exceed values

DOXYCYCLINE r - 0.9266 n - 44

4.00

- E ? 3.00 . U

s 2.00

5 3 L -

0. ‘ 0. 1.00 2.00 3.00 4.00

WLC-me thod pglrnl

MINOCYCLINE r - 0.9679 n - 23

0. ‘ 0. 1 .oo 2.00 3.00

t-PLC-mthod /‘9/ml

Figure 4. Plasma concentrations determined by high performance liquid chromatography method Wml) vs agar diffusion method (Irglml).



4520 PIJPEIU ET AL.

1 .oo

.80

.60

.40

.20

0.

corresponding to about 10 m a g for all tetracyclines. For DC, however, it was essen- tial to measure at 270 nm. At 350 nm much more matrix interference was observed. The tetracycline contents of the feed shown in Table 3 were corrected for these values of the blank feed.

In conclusion, administration of DC and MC at a dose of 13 and 18 mg per kilogram of BW per day as a 400 mg/kg feed medication resulted in plasma levels ranging from .71 to 1.14 pg DC/d and .43 to 1.05 pg MC/ml, respectively. For 0°C a dose of 81.5 mg per kilogram of BW per day (1,600 m a g feed medication) proved necessary to achieve similar plasma levels. In humans the absorption of DC and MC compared with OTC is reduced less by food, dairy products, and metals (Neuvonen, 1976; Welling et al., 1977; Aron- son, 1980; Saivina and Houin, 1988). More- over, mean MIC values of some porcine bacterid respiratory tract pathogens for the two newer tetracycline congeners are twice as low as for OTC (F5jpers et d., 1989). So, based on

OTC Feed Medication

- & & L & L L & U L & T T 1

T A 1 f A

T 1 A T

T i -

T i f -

-

A I 1 I 1 1 I 1 I I I I -

+ - .- s Y a L +.r E 0

0 0

0 oc

A

plasma levels and MIC values, DC and MC could be good alternatives for OTC to treat respiratory tract infections. Moreover, in other species lung to plasma ratio for the two newer lipophilic tetracyclines proved to be p t e r than 1, whereas the elimination half-lives were longer than that of OTC (Schach von Wittenau and Delahunt, 1966; Blanchard et al., 1975; Riond and Riviere, 1988; Saivin and Houin, 1988).

It should be emphasized that information about the effects of DC and MC in pigs should be interpreted with caution. As yet, locally obtained concentrations in the lung, pharmacokinetic data, and clinical efficacy are unlmown. Further research to obtain those data seems to be necessary.

implications

Feed concentration of 1,600 mg of oxytetracycline per kilogram of feed, equivalent to 81.5 mg of oxytetracycline per kilogram of body weight per day, proved to achieve mean

Figure 5. Mean plasma oxytetracycline (OTC) concentrations (pglml) (n = 8) of pigs fed a diet fortitied with 1,600 mg of OTC per kilogram of feed.



FEED MEDICATION WITH TETRACYCLINES IN PIGS 4521

1 .oo

.80

.60

.40

.20

0.

+ Y

DC Feed Medication

s S s S i & C U + C 0 T 1 P T

0 T

- T 0 T T l 0 1 1

y e -

-

-

A I I I I I I I I I I I

0 n

Hours Figure 6. Mean plasna doxycycline @C) concenhations Wglml) (n = 8) of pigs fed a diet fortified with 300 mg of

Dc per kilogram of feed.

minimal inhibitory concentrations for porcine bacterial respiratory tract pathogens. After administering 300 mg of doxycycline per kilogram of feed (1 1.5 mg of doxycycline per kilogram of BW per day) and 400 mg of minocycline per kilogram of feed (18 mg of minocycline per kilogram of BW per day) minimum plasma levels in the steady state exceeded mean bacterial minimal inhibitory concentration values. Based on plasma levels and known in vitro activity, doxycycline and minocycline could be good alternatives for oxytetracycline to treat respiratory tract infections in pigs. However, further research to obtain data about clinical efficacy is necessary.

Llterature Cited

Aronson, A. L. 1980. Pharmacotherapeutics of the newer tetracyclines. I. Am. Vet. Med. Assoc. 176:lMl.

Barza, M., R. B. Brown, C. Shanks, C. Gamble and L. Weinstein. 1975. Relation between lipophilicity and pharmacological bebaviour of Minocycline, Doxycy- cline, Tetracycline and Oxytetracycline in dogs. Antimicrob. Agents Chemother. 8713.

Bergan. T. 1978. Kinetics of Tissue Penetration. Sand. J. Infect. Dis. Suppl. 1436.

Black. W. D. and R. D. Gentry. 1984. The distribution of oxytetracycline in the tissues of swine following a single oral dose. Can. Vet. J. 25:158.

Blauchard, P., M. Rudhardt and J. Fabre. 1975. Behaviour of doxycycline in the tissues. Chemotherapy 21 (Suppl. 1):8.

Brander, G. C., D. M. Pugb and R. J. Bywater. 1982. Veterinary Applied Pharmacology and Theraputics (4th Ed.). Bailliere Tindall. London.

Counotte. G.H.M., T. Eefting and A. Bo& 1984. Stability and distribution of oxytetracycline hydrochloride during the manufacture and storage of pig-rearing pellets under field conditions. Neth. J. Vet. Sci. 109: 339.

de Leenheer, A. P. and H.J.C.F. Nelis. 1979a. Doxycycline determination in human serum and urine by high performance liquid chromatography. J. Pharm. Sci. 68: 999.

de Leenheer, A. P. and HJ.C.F. Nelis. 1979b. Liquid chromatopphic deterahation of minocycline in human serum. J. Pharm. Sci. 66:1527.

Dornbush, A. C. and A. Abbey. 1972, Microbiological assay of tetracyclines. In: P. Kavanagh @d.) Analytical Microbiology. Vol. IT. pp 365-383. Academic Press, New York.

Hall, W. F., D. P. Bane and C. R. Kilroy. 1988. The use of oxytetracycline medicated feed to prevent pneumonia caused by Pasteurella multocida type A. Proc. of the loth Congress IPVS. p 61. Rio de Janeiro, Brazil.

Hall, W. F.,T. S. W e n , D. P.Bane, R.F.Bevill and G. D. Koritz. 1989. Plasma concenbrations of oxytetracy- clime in swine after administration of the drug intramuscularly and orally in feed. J. Am. Vet. Med. Assoc. 194:1265.

m y , C.R., W.F.Hall.D.P.Bane,RF.BevillandG.D. Koritz. 1990. Chlortetracycline in swine - bioavaila-



4522 PlJPERs ET AL.

J.H.M. Verheijden. 1991. The intluence of disease on feed and water consumption and on pharmacokinetics of orally adminismed oxytetracycline inpigs. J. Anim Sci 69:2947.

Powers. T. E., K. J. Varma and J. D. Powers. 1984. Selecting therapeutic concentrations: Minimum inhibitory concentrations vs subminimum or supraminimum inhibitory concentrations. J. Am. Vet. Med. Assoc. 185: 1062.

prescott, J. F. and J. D. Baggot. 1988. Antimicrobial Ihmpy in Veterinary Medicine (1st Ed.). pp 9-16. Blackwell S c i e n ~ c Publications. Loadon.

Riond, J. L. and I. E. Rivim. 1988. pharmacology and toxicologyof doxycycline. Vet. Hum.ToxicO1.30:431.

Saivin, S. ami G. HOnin. 1988. clinical Plmmacokin&s of Doxycycline and Minwycline. Clin. Pharmacokinet 15355.

Schach von Witmu, M. and C. S. Delahunt. 1966 The dishibution of tetracyclines in tissues of dogs after repeated oral administration. J. phannecol. Exp. Iher. 152 164.

Shimizu. M., IC. Kmiori. T. Sakano and T. Terashima 1982. Antibiotic sasceptability of Haanophilur pleuropneu- mmae and Pasteurella dtoc ida isolates from swine. Jpn. J. Vet. Sci. M359.

Welling,P.G..P.A.Koch,C. C.LaaandW.A.Craig. 1977. Bioavaihbility of Tetracycline and Doxycycline m Fasted and Nonfasted Subjects. Antimicro b. Agents chemother. 11:462.

Welling, P. G. and F.L.S. Tse. 1982. The influence of food on the &Sorption Of antimicrobial agents. J. An- timicrob. Chemother. 9 7 .

Wood. M. J., W. Farrell, S. Kattan and J. D. Williams. 1975. Activity of minocycline and tetracycline against rtspiratory pathogens related to Mood levels. J. Antimimob. Chemother. 1:323.

bility and pharmacokinetics in fasted and fed pigs. J. Vet. pharmacal. Ther. 13:49.

Kniffen,T.S.,D.P.Bane,W.F.Hall,G.D.KoritzandR.F. Bevill. 1989. Bioavailability. pharmacokinetics, and plasma concentration of tetracycline hydrochloride fed to swine. Am. J. Vet. Res. 50518.

Kunesch, J. P. 1986. Therapeutics. In: A. D. Leman, B. Straw, R. D. Glock, W. L. Mengeling, R . H B Penny and E. Scholl (Ed.) Diseases of Swine (6th Ed.). pp 805412. Iowa State Univ. Press, Ames.

Limpoka, M. 1978 Disposition of oxytetracycliae in cattle, sheep and swine. FILD. 'Ihasis. Univ. of Illinois, Urbaaa-Champaign.

Uartinez, E. E. and W. Shimoda. 1988. Liquid chromato- graphic determination of tetracycline residues in animal feeds. J. Assoc. off. Anal. Chem. 71:477.

Mercer, H. D., R. H. Teske, P. E. Long and D. H. Showalter. 1978. Drug residues in food anhnals. II. Plasma and tissue kinetics of oxytetracycline in young cross-bred swine. J. Vet. -01. llm. 1:119.

Mevius, D. J., L. Vellenga, H. J. Breukink, J3.M. Nouws, T. B. Vree and F. Driessens. 1986. PfiarmaCoLinetics and renal clearance of oxytetracycline in piglets following intravcnoos and oral administration. Vet. Q. 8:274.

Moats, W. A. 1988. Inactivation of antibiotics by heating in foods and other substrates - A review. J. Food Rot. 5 1: 491.

Neuvonen, P. J. 1976. Interactions with the absorption of tetracycline. Drugs. 11:45.

Pijpers, A., B. van Klingeren, E. J. Schoevers, J.H.M. Verheijden and A.S.J.P.A.M. van Miert. 1989. In vitm activity of five tetracyclines and some other antimi- bial agents against four porcine respiratory tract pathogens. J. Vet. Pharmacol. Ther. 12267.

Pijpers, A., E. J. Schoevas, H. van Go& L.A.M.G. van Leengoed, IJR. Visser, A.S.J.P.A.M. van Mi& and



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