Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants

Veterinary Quarterly ISSN: 0165-2176 (Print) 1875-5941 (Online) Journal homepage: http://www.tandfonline.com/loi/tveq20 Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants J.F.M. Nouws & G. Ziv To cite this article: J.F.M. Nouws & G. Ziv (1979) Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants, Veterinary Quarterly, 1:1, 47-58, DOI: 10.1080/01652176.1979.9693720 To link to this article: https://doi.org/10.1080/01652176.1979.9693720 Copyright Taylor and Francis Group, LLC Published online: 01 Nov 2011. Submit your article to this journal Article views: 79 View related articles Citing articles: 15 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalinformation?journalcode=tveq20 Download by: [37.44.207.8] Date: 20 November 2017, At: 12:51

Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants J. F. M. Nouwsl and G. Ziv2 Downloaded by [37.44.207.8] at 12:51 20 November 2017 SUMMARY Serum chloramphenicol concentrations were determined by microbiological and chemical assay methods in cows, ewes, and goats treated parenterally with seven different veterinary parenteral chloramphenicol products, including the water soluble sodium succinate ester of chloramphenicol and solutions of 20%, 25% and 50% of chloramphenicol base in various organic solvents. Serum drug concentrations were analyzed for the effect of product formulation differences, dosage, whether the drug was administered i. m. at a single body site or to two sites, and the method of assay, on the absorption from the injection site, peak drug levels, and the persistence in serum of effective concentrations of the drug i.e. 5 to 10 ug 1 ml. Although differences were observed among the 6 products containing chloramphenicol base in respect to absorption rate and peak serum drug levels, and although these differences significantly influenced the persistence of microbiologically-active serum drug concentrations at the level of> 10 pg1 ml, they did not at the level of > 5 lig/ ml. In the animal species examined, injections given at 2 sites appeared to influence the duration of predetermined serum drug levels more than the differences among the products in respect of the absorption and elimination rates from serum, the peak serum concentrations, and the dose. The shapes of the concentration-to-time curves in cows and ewes injected with the same dose of a given product were essentially the same, but they were different in goats. Serum chloramphenicol concentrations measured chemically after treatment with chloramphenicol base were 20% to 46% higher than those measured microbiologically. For 60 minutes after the sodium succinate ester had been administered i. v. and Lin, to ewes, the chemically determined chloramphenicol levels were more than twice as high as the respective concentrations determined by microbiological assay, but thereafter, the magnitude of those differences was not greater than observed after treatment with chloramphenicol base. Intramuscular bioavailability of the products containing chloramphenicol base injected at 2 sites was rather poor (51% to 80.5% of thedose)and even lower values were calculated after injection at a single site. Results are briefly discussed of the effect of dosage form on the persistence of microbiologically effective serum drug levels. A dose of at least 50 mg 1kg to be administered i.m. at two sites are essential prerequisits for chloramphenicol therapy in ruminants. I Meat Inspection Service (Vleeskeuringsdienst), liavenweg 2, Nijmegen, the Netherlands. 2 Ministry of Agriculture, Kimron Veterinary Institute, Bet Dagan, Israel. THE VETERINARY QUARTERLY, VOL. 1, No. I. JAN. 1979 47

Downloaded by [37.44.207.8] at 12:51 20 November 2017 INTRODUCTION Results of experiments concerning the concentration of antibiotic residues at the intramuscular (i.m.) injection sites in pigs and cattle showed that after treatment with different antibiotics, or several formulations of a given antibiotic, the drug persisted at the injection site for varying periods of time (3, 5). Thus, after the i.m. injection of different penicillin and dihydrostreptomycin products, residues were detected at the injection site during a short period only, whereas after rather similar doses of oxytetracycline, tylosin, or chloramphenicol had been given, residues were detectable for considerably longer periods (5). Slow and erratic absorption of the administered dose was considered to be responsible for the latter findings (5). The present report deals with serum chloramphenicol concentrations and the i.m. bioavailability of chloramphenicol in several ruminant species. Chloramphenicol has been selected for these studies because it is presented to the practitioner in several forms, i.e. as an ester, which is readily soluble in water, and as the base, soluble in variety of organic solvents. Furthermore, since the drug can be assayed chemically and microbiologically, it was interesting, by means of these two Table I. methods, to examine and to compare the rate and extent of absorption and bioavailability after i.m. treatments. MATERIAL AND METHODS Type of parenteral veterinary chloramphenicol formulations tested. Seven parenteral chloramphenicol products, including the water soluble sodium succinate ester of chloramphenicol, and solutions of 20%, 25%, and 50% of chloramphenicol base in different organic solvents were available (Table 1). Studies were conducted of 14 dairy cows (450 to 595 kg each), 13 ewes (50 to 65 kg each), and 4 goats (20 to 25 kg each). Several of the animals were treated with more than one product (cross-over experiment). Intramuscular injections were given into the upper 1/3 of the neck; the dose was either administered to one side (single injection site) or it was divided equally into 2 parts and administered to the left and right sides (two injection sites). Products 1 to 7 were administered i.m.; Products I and 5 were also given intravenously (i.v.) Further details concerning the number of animals treated with each product, number of injection sites, and the dose applied are given in Tables 2 to 5. After i.m. injection, blood samples were collected from the jugular vein at the following periods (minutes): 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 600, 720, and in several of the trials also 840. Blood samples were taken in the first hour at 10-minute intervals after i.v. treatment; thereafter the sampling periods were as for the i.m. treatment. Blood was allowed to clot at room temperature and within 24 hours of sampling the serum was separated by centrifugation. Serum samples were kept at 20 C. The concentrations of chloramphenicol in samples collected in several experiments were determined chemically (6) and microbiologically (6). Other samples were assayed either chemically or microbiologically, as detailed in Tables 2 to 5. Product Manufacturer Composition Sol vent 1 Mycofarm,Del ft. Chl orampheni col succinate sodium Distilled water 2 Vi tamed,tel Aviv. Chlorampheni col base,20%.lot 117427 Organic sol vent 3 Abic Ltd. Chloramphenicol base,20%.lot 596346 Organic solvent 4 Mycofarm,Del ft. Chlorampheni col base,25%.lot 75E18 Methylpyrrolidine 5 Intervet,Boxmeer. Chl orampheni col base,25%.lot 341021 Dimethylacetamide 6 Abic Ltd. Chloramphenicol base,50%.lot 121576A Organic solvent 7 Abic Ltd. Chloramphenicol base,50%(experi mental )Organic solvent 48 THE VETERINARY UARTERLY. VOL. I, No, I. JAN. 1979

Downloaded by [37.44.207.8] at 12:51 20 November 2017 Calculations of several kinetic variables, i.e. the absorption half-life (T1/2abs,), the elimination halflife (Ty2,6), peak drug concentration (Cmax), time of Cmax (Tmax), and the area under the concentration-to-time curve (AUC) from the first posttreatment sampling to 720 minutes after treatment, were made from serum drug level data derived from microbiological assay, or chemical assay or from both assay procedures as described earlier (14). For calculating these variables, first-order processes for absorption and elimination were assumed. RESULTS AND DISCUSSION Serum chloramphenicol concentrations in cows treated with products 2, 3, 5, and 6 are detailed in Table 2 and the mean values are presented graphically in Fig. I. Products 2, 3, and 6 were administered at a dose level of 30 mg/ kg in a cross-over trial involving 5 cows, and the Cthax values calculated were 9.8, 8.2, and 9.2 Ag/ ml, respectively (Table 5). These values were not significantly different at the 95% level. However, Tmax values were significantly different, being 192, 131, and 249 minutes for products 2, 3, and 6, respectively. The calculated AUC for each of these products were very similar: 4203, 3505, and 4330 (mg/ liter)/ minutes (Table 5). Therefore, apart from a small difference in the Tmax values, and hence in the absorption rates, these 3 products behaved similar in cows, and their relative bioavailabilities as measured by com- Paring of the AUC values, were similar also. Product 5 was injected (two sites) to two other cows at a slightly higher dose (35.6 ± 2.5 mg/kg) (Table 2) and the Cmax and AUC values did not differ from the respective values calculated for products 2, 3, and 6. However, after treatments with product 5, peak serum drug levels were reached 6 hours later and the absorption rate was considerably slower, compared to the other 3 products (Fig. 1). Product 5 was administered to two other cows (two sites) at 18 mg/ kg, i.e. approximately half the former dose, and the Cmax was lower (6.2 pg/ ml), and after the same dose had been injected at a single site, the Cmax was lower still (4.6 I-tg/ m1). On the basis of Fig. 1, estimates were made of the duration of serum chloram- Phenicol levels, as determined by chemi- THE VETERINARY QUARTERLY. VOL. I. No I. JAN. 1979 cal assay, persisting at concentrations > 10 pg/ ml. Such levels were maintained for 3 hours after product 5 was injected i.v. at 9 mg/kg, but was not achieved with product 5 after i.m. injection. At a dose level of 30 to 35 mg/ kg administered i.m. at two sites, serum blood concentrations?-5 1./g/ ml were maintained for 71/2 hours following treatment with product 2; during 6 hours after treatment with product 3; approximately 10 hours after injection of product 6, and least 18 hours following treatment with product 5. After product 5 was injected i.m. at approximately 18 mg/ kg as a single site administration, serum chloramphenicol concentrations were below 5 pg/ ml, but when the same dose was administered to two sites, these levels (> 5 pg/ ml) were maintained for approximately 6 hours (Table 2). It appears from the data obtained in cows that the route of administration, i.e. wether i.v. or i.m., and the number of sites of i.m. drug application are major determinants for maintaining serum drug levels in the desired range of 5 to 10 pg/ ml, whereas a 2-fold increase in the i.m. dose results in a very small increase in the persistence of the serum drug levels. Furthermore, although the products differed in the rates of absorption, these differences exerted only a minor effect on the length of time during which the serum chloramphenicol concentrations were maintained at 5 pg/ ml. Table 3 presents data gathered from ewes given a standard dose of 50 mg/ kg. Five different formulations were administered i.m., allowing some comparisons to be made of effect of dosage form and number of injection sites on serum drug levels, irrespective of the dose. Injection of chloramphenicol sodium succinate (product 1) resulted (chemical assay) in a very rapid absorption rate (T1/2abs. = 5.3 minutes); Cmax was approximately 30 pg/ ml at 21 minutes, but the drug was eliminated very rapidly from the serum (T1/2/3 = I 1 1 minutes). These values are very close to those reported previously in sheep (10, 11). It is very doubtful whether the T1/2abs. of the drug would have been shorter and the Cmax higher if product 1 had been injected at two sites. Chemical 49

8 Downloaded by [37.44.207.8] at 12:51 20 November 2017 18 k I Fig. Mean serum chloramphenicol concentrations after intramuscular and intravenous injection of several chloramphenicol preparations. 16 141 12 I 10 111011110Nial 4p Product Dose 30 2( n=5; i.m.);chem. assay. mg/kg. *WMAIWOM Product 3 ( n=5; i.m. ) ;chem. assay. mg/kg. Op: Product :urt i.m.);chem. assay. Dose 30 mg/kg. 1. Product 5(n=2;1.m.);chem. Dose 18 mg/kg. assay. Product 5(n=2;i.m.);chem. assay. Dose 36 mg/kg. 126-- idem ;bioassay. -CI- Product 5( n=2; i. v. ) bioassay. Ddse 9 mg/kg. EF- 8 idem ;chem. assay. 6 4 a---.0 ' 4 -- - h.4.40 --11--4 0 --- 60 120 180 240 300 360 420 480 540 600 660 720 1080 MINUTES AFTER TREATMENT. ' '

-I = m <, -4 m x >74. 00 a>x, - - m.< < 0. r ZP 7 L. > 7 ẓ.. CA -- Downloaded by [37.44.207.8] at 12:51 20 November 2017 Table 2. Serum chloramphenicol concentrations after intramuscular and intravenous injections of several chloramphenicol preparations in dairy cows. PRODUCT 2 3 6 5 5 5 5 MODE OF Two sites Two sites Two sites One site Two sites APPLICATION Two sites i.m.;n=5 i.m.;n=5 Intravenous i.m.;n=5 i.m.;n=2 i.m.;n=2 i.m.;n=2 n=2 DOSE MG/KG 30 30 30 17.9 18.1 35.6 + 2.5 9.0 + 0.6 TIME IN Time in Time in MINUTES (b) (b) (b) min. (a) (b) (a) (b) (a) (b) min. (a) (b) V_ Concentrati on,ug/m1 n=1 n=2 s erum JO 15 3.18 2.25 1.43 15 1.18 0.78 1.28 1.29 1.17 1.83 8 17.44 21.0 (0.99) (0.53) (0.45) (0.02) (0.28) (0.10) (0.08) (0.35) (1.68) (5.2) 30 5.44 3.59 4.41 30 2.22 1.47 2.26 2.75 1.78 3.04 15 16.9 18.0 (0.69) (0.49) (0.42) (1.34) (0.29) (0.17) (0.46) (1.00) (5.6) (3.6) 60 8.10 7.10 7.16 45 2.56 1.98 3.61 4.43 2.19 4.24 20 13.0 17.0 (1.36) (1.07) (0.97) (1.1) (0.38) (0.30) (0.30) (0.69) (3.7) (5.1) 120 9.31 8.12 7.99 60 3.46 3.11 3.90 4.29 2.84 4.70 30 14.1 16.5 (0.94) (0.54) (0.44) (2.16) (0.40) (0.14) (0.71) (1.16) (3.68) (2.6) 180 9.61 7.72 8.81 90 2.84 2.51 3.95 4.81 3.12 5.59 40 13.0 13.4 (1.25) (1.14) (0.46) (1.13) (0.39) (0.12) (0.35) (0.54) (4.3) (0.2) 240 7.63 6.43 9.16 135 2.89 3.06 4.42 5.61 3.44 6.03 50 11.7 13.2 (0.50) (0.52 ) (0.41) (1.29) (0.05) (0.69) (0.34) (0.91) n=2 (4.1) (3.3) 360 5.86 5.34 8.68 300 2.18 3.95 4.56 5.53 3.85 6.63 60 10.0 13.1 (0.58) (0.83) (0.46) (0.66) (2.16) (0.31) (0.01) (0.32) (0.57) (2.7) (2.8) 480 5.19 4.42 7.72 315 2.18?.40 4.57 5.73 3.98 8.09 135 7.4 10.8 (0.38) (0.76) (0.55) (0.67) (1.75) (0.35) (0.14) (0.40) (1.75) (2.8) (3.1) 600 3.39 2.36 6.49 450 2.08 2.45 4.45 5.32 3.95 7.41 165 6.2 8.3 (0.49) (0.65) (1.00) (1.72) (0.07) (0.85) (0.62) (0.60) (3.7) (1.7) 720 1.90 1.46 4.31 1080 2.15 1.62 1.86 3.86 3.45 6.04 240 4.8 7.4 (0.40) (0.47) (0.78) (0.75) (0.81) (2.29) (0.15) (0.09) (3.5) (3.3) (a) Bioassay. (b) Chemical assay. (c) Mean and standard deviation in brackets. n = Number of cows involved. '. 2

CAI 1 ;n-- <., mmm 5: > x! 0 a > x,m m 7' < 0r 7 lit P 7 L. >, 3 Downloaded by [37.44.207.8] at 12:51 20 November 2017 Table 3. Mean chloramphenicol concentrations in serum of ewes after intramuscular or intravenous administration of several products at a dose of ± 50 mg/ kg live weight. (Mean and standard deviation). CHLORAMPHENICOL, - PRODUCT 1 5 5 4 7 6 3 2 1 NUMBER OF EWES n = 6 n = 6 n = 6 n = 9 n = 9 n = 4 n = 4 n. 4 n = 4 NUMBER OF INJEC-. One site Two sites One site One site One site Two sites Two sites Two sites Intravenous TION SITES (i.m.) (i.m.) (i.m.) (i.m.) (i.m.) (i.m.) (i.m.) (i.m.) TIME IN MINUTES Time in AFTER INJECTION (a) (b) (a) (a) (a) (a) (a) (b) (a) (b) (s) (b) minutes (a) (b) Chloramphenicol concentration in ug per ml serum.(c) 15 13.0(3.0) 27.1(6.8) 6.1(3.9) 5.1(3.8) x, x x x x x 10 24.3(2.2) 66.6(3.7) - 30 14.1(4.1) 27.0(7.9) 11.8(3.8) 4.7(2.6) 5.)(2.7) 5.3(3.2) 2.1(0.36) 2.5(0.48) 2.5(0.45) 4.0(0.46) 3.6(0.77) 5.2(0.62) 20 21.5(1.5) 50.9(9.0 60 14.3(4.4) 19.7(5.5) 12.6(5.0) 6.3(2.0) 9.6(7.1) 7.7(5.8) 2.7(0.51) 4.1(0.67) 3.2(0.60) 4.9(0.94) 4.5(0.54) 6.0(0.60) 30 21.0(2.0) 34.6(1.0 120 9.3(1.6) 13.9(2.9) 14.6(6.6) 8.5(3.3) 10.9(5.7) 8.0(6.5) 3.6(0.75) 5.3(0.77) 4.4(0.83) 6.3(1.02) 5.4(0.75) 6.9(0.70) 40 16.0(2.8) 24.0(0.0 180 7.2(1.8) 9.6(2.7) 18.0(10.6) 9.3(4.7) 11.4(4.9) 7.8(8.0) 4.9(0.73) 7.6(1.04) 5.7(0.38) 8.5(0.98) 6.2(0.43) 8.9(0.74) 50 17.2(2.7) 22.4(8.1) 240 6.0(1.3) 7.8(1.6) 14.6(8.3) 7.5(3.3) 9.3(6.4) 6.8(6.6) 6.1(0.22) 8.9(0.30) 6.5(0.38) 10.2(0.7) 7.1(0.49) 10.1(0.68) 60 15.3(4.6) 21.0(3.0 300 3.7(1.2) 4.7(1.7) 12.5(2.7) 7.0(3.6) 5.6(3.0) 7.9(9.2) x x x 90 8.7(2.7) 12.2(1.9) 8 360 2.2(0.2) 3.0(0.7) 10.0(3.9) 8.4(5.9) 5.8(4.9) 4.7(4.6) 6.5(0.19) 9.0(0.39) 6.3(0.36) 8.9(0.51) 6.9(0.44) 10.0(0.88) 120 6.0(1.6) 14.4(5.4) 420 1.1(0.1) 2.0(1.2) x x x L x x x x x 180 4.4(1.2) 6.0(0.3) 480,1.0 1.7(1.1) 7.9(4.4) 7.4(4.5) 3.0(2.5) 4.7(4.5) 5.9(0.30) 8.5(0.77) 4.7(0.75) 6.7(1.08) 5.5(0.70) 8.3(0.91) 240 2.5(0.8) 2.6(0.6) 600 x x 5.0(2.8) 5.3(2.5) 1.9(0.7) 2.8(2.7) 5.2(0.62) x 3.8(0.70) x 4.6(0.57) x 300 1.5(0.6) 4.2(3.0) (n=2) 720 x x x x x x 4.3(0.66) 5.6(0.45) 2.5(0.35) 3.9(0.68) 3.5(0.97) 5.0(1.26) 360 <1.0 4.5(2.4) (n=3) 840 x x x x x x 2.9(0.64) 3.8(1.18) 1.6(0.28) 2.6(0.33) 2.2(0.75) 3.2(0.79) 420 <1.0 2.8(1.2) 480 <1.0 1.6(0.28) (a) Bioassay. (b) Chemical assay. (x) Not determined. (c) Mean and standard deviation in brackets. i.m. = intramuscular;i.v. = intravenous. '

Downloaded by [37.44.207.8] at 12:51 20 November 2017 analysis was carried out on serum samples taken after the injection of products 2, 3, and 6, and although the ewes were given a larger dose than the cows (50 mg/ kg as compared to 30 mg/ kg), mean T1/2abs., Cmax, Tmax, and T 1/2 J3 values in cows and ewes were not significantly different (Table 5). A comparison of chloramphenicol concentrations as determined chemically and microbiologically in serum samples of ewes after the i.m. injection of products 2, 3, and 6, and in cows after treatment with product 5, all of which contain chloramphenicol base, shows that the values obtained by chemical assay were consistently higher (20% to 40%) than those measured microbiologically. Differences among these 4 products in this respect were not observed. Examination of the data from the ewes treated i.m. with product 1 (Table 3) shows that during the first 30 minutes post treatment serum chloramphenicol concentrations (chemical assay) were 2-fold higher than those obtained microbiologically, and that after the i.v. injection of product 1, these differences were even greater. Approximately 2 hours after the i.v. and i.m. injection of product I and thereafter, the magnitude of the differences of serum chloramphenicol concentrations resulting from the 2 assay procedures progressively became smaller and were similar to the extent of the differences observed after treatment with chloramphenicol base. In goats treated with the succinate ester of chloramphenicol i.m. and i.v, (Table 4), chloramphenicol serum concentrations determines chemically were consistently more than twice as great as those determined microbiologically. It is well recognized that the succinate ester of chloramphenicol is microbiologically inactive (10) and that in vivo hydrolysis occurs rapidly. Our data suggest that maximum hydrolysis of the ester in vivo occurs after 60 to 120 minutes in ewes and after a considerably longer time in goats. A comparison ofserum chloramphenicol concentrations after treatment with different formulations of the drug in relation to potential therapeutic values can only be made from data obtained by means of microbiological assay procedures, because chemical methods measure different proportions of the microbiologically inactive metabolites as well. Microbiologically determined concentrations of chloramphenicol can, therefore, best be used for making comparisons of persistence of 'effective' serum drug levels. Serum chloramphenicol concentrations obtained by chemical assay can be used for the same purpose if they are considered to correspond to approximately 50% to 80% of the microbiologically active drug. Such comparisons indicate that in cows, products 2, 3, 5, and 6 injected i.m. produced almost equivalent microbiologically active serum chloramphenicol concentrations, but in ewes treatment with products 4 and 5 results in higher values (Table 3). Products 4 and 5 administered to goats resulted in higher Cmax values than did product 7 (Table 4). The slow rate of absorption of product 7 from the i.m. injection site was the determinant factor for the shape of the concentration-to-time curve and this was not altered by a 2-fold increase in dosage. Microbiologically active serum chloramphenicol concentrations?.10 pg/ ml were maintained in ewes for 5.5 hours after injection of product 5' at 2 sites, and these levels were not reached after the drug was administered at one site. Similar levels were maintained in the serum of ewes for 11/2 hours, but only after treatment with product 1, and for 1 hour after products 1 and 4 had been administered i.m. to goats (Table 4). On the basis of persistence of concentrations of 5.0 mg/ ml of microbiological active serum chloramphenicol, products 2 to 7 administered i.m. either to two or to a single site in ewes at 30 to 50 mg/ kg appear to be very similar. In general, the i.m. bioavailability of all chloramphenicol-base products was low. Thus, on the basis of the AUC measured microbiologically in ewes injected with product 1 i.v., the absolute bioavailability of the i.m. doses were calculated to range from 51.0% for product 3 to 80.5% for product 5 (2-site injection). A lower percentage of the doses was available for distribution and elimination from the body THE VETERINARY QUARTERLY. VOL. I. No. I. JAN. 1979 53

Downloaded by [37.44.207.8] at 12:51 20 November 2017 LA 4=, Table 4. Mean serum chloramphenicol concentration after a single intramuscular or intravenous injection of several products in a cross-over study involving 4 goats. PRODUCT 1 4 7 7 1 (c) DOSE MG/KG I.M.:50 mg/kg I.M. : 50 mg/kg I.M. : 50 mg/kg I.M. : 100 mg/kg Intravenous: 50 mg/kg TIME IN MINUTES Time in AFTER INJECTION. (a) (b) (a) (a) (a) minutes (a) (b) CHLORAMPHENICOL CONCENTRATION IN MCG PER ML SERUM(d) 15 9.9(1.0) 31.5(1.4) 3.7(0.72) 1.1(0.67) x 10 26.0(4.3) 74.3(6.4)n=2 30 15,8(3.2) 33.2(2.2) 11.5(2.9) 2.2(1.3) 5.0(2.7) 20 20.5(1.0) 38.7(5.9) 60 12.9(2.9) 29.2(3.2) 15.3(1.2) 3.2(1.1) 5.9(2.5) 30 17.4(4.4) 43.1(1.6)n=2 _ 120 9.6(1.9) 18.4(1.5) 8.5(6.7) 2.5(1.5) 6.1(2.3) 40 17.5(2.1) 31.5(6.5) 180 7.6(1.5) 13.6(3.5) 6.5(9.2) 2.6(1.1) 5.9(2.6) 50 17.9(1.5) 26.7(5.0) 240 5.5(0.60) 11.1(3.2) 2.6(3.6) 1.7(1.7) 4.7(1.8) 60 14.4(2.1) 21.5(3.3)..-1 IT, < --. m x5, > 300 3.6(1.3) 10.0(6.6) <1.0 1.24(1.1) 4.5(2.8) 90 8.4(0.9) 20.6(6.0) 360 2.4(0.3) 4.3(0.9) <1.0 T 3.7(1.8) 120 6.9(0.3) 16.7(6.9) 420 1.4(0.4) 26(1.3) x T 3.3(1.5) 180 3.6(0.6) 10.6(2.0)..c 9' > w-4 m 7. ṛ < < o r r.?.,- r t... / )..-a!.1! 480 <1.0 3.2(1.5) x T 1.3(0.4) 240 2.6(0.9) 8.2(0.7) 600 x x x T T 300 2.2(0.7) 6.5(1.5) 720 x x x T x 360 2.1(0.5) 4.4(0.7), % 420 <1.0 4.2(0.4) 480 <1.0 2.8(1.4) 600 <1.0 1.4(1.1) (a) bioassay. (b) chemical assay. (c) i.m.=intramuscular.(d) standard deviation in brackets. x = Not determined. T = trace.

Downloaded by [37.44.207.8] at 12:51 20 November 2017 Table 5. Disposition kinetics of chloramphenicol in ruminants following intramuscular administration of several formulations. (Mean values) PRODUCT SPECIES NO No of animals Dose mg/ kg No of ABSORPTION injection HALF-LIFE(T, ) (minutes) 2CL sites chem. assay ELIMINATION HALF-LIFE(T) (minutes) 2P chem. assay PEAK DRUG CONCENTRATION (Cmaxin ugml) chem. assay TIME OF AREA UNDER THE CURVE C (Iirirn(uTt: ) chem. assay mg/liter/minutes) ( (AUC) bioassay bioassay bioassay bioassay bioassay chem. assay 1 ewes 6 50 1 9.3 5.3 109 111 17 30 36 21 3355 5117 goats 4 50 1 18 5.6 88 112 20 36 52 25 3280 6230 2 cows 5 30 2 x 33 x 252 x 9.8 x 192 x 4203 ewes 4 50 2 71 66 360 298 7.2 10.2 258 244 3650 4680 3 cows 5 30 2 x 49 x 242 x 8.2 x 131 x 3505 ewes 4 50 2 64 56 246 302 6.5 10.2 240 240 3582 5279 4 ewes 9 50 1 32 x 167 x 12.2 x 156 x 3810 x goats 4 50 1 18 x 74 x 15.6 x 50 x 1981 x 5 ewes 6 50 1 36 x 643 x 9.3 x 140 x 4366 x ewes 6 50 2 47 x 296 x 18.9 x 140 x 5654 x 6 cows 5 30 2 x 62 x 448 x 9.2 x 249 x 4330 ewes 4 50 2 92 115 447 388 6.6 9.3 362 371 4046 5681 7 ewes 9 50 1 40 x 298 x 9.9 x 108 x 3491 x goats 4 50 1 13 x 399 x 3.3 x 62 x 655 x goats 4 100 1 48 x 262 x 7.0 x 136 x 2147 x (x) = Not determined.

after these products were administered at a single site. Large individual variations in serum drug levels after i.m. treatment were a characteristic finding for all the products investigated, but they appeared to be less pronounced after treatment with the sodium succinate ester and after the other products were administered at two sites. These variations probably reflected the erratic nature of the absorption process of i.m. administered chloramphenicol and may have some clinical and therapeutic relevance. Interestingly, serum chloramphenicol concentration-to-time curves for each animal, and their means, showed a characteristic 'hump' approximately 60 minutes after i.v. injection (Fig. 1-3). CHLORAMPHENICOL CONCENTRATION, Ug /ML SERUM. Downloaded by [37.44.207.8] at 12:51 20 November 2017 ct 8 C.1 CV 8 CJ 56 THE VETERINARY QUARTERLY. Vol.. I. No. I. JAN 1979

10 50, k-4chloramphenicol succlnate;chem. assay. Intravenous.Dose 50 mg/kg. Aronssi 0-0 11---11 idem ;bioassay. Chloramphenicol succinat;cham. assay. Intramscular.Dose 50 mg/kg. idem ;bioassay. Product 4(dose 50 mg/kg );bioassay..4(...40( Product 7(dose 50 mg/kg) ;bioassay. ilmessmamit Product 7(dose 100%9/kg) ;bioassay. c) 10 Downloaded by [37.44.207.8] at 12:51 20 November 2017 1.0 I _I 60 120 180 240 300 360 420 480 540 600 MINUTES AFTER TREATMENT. Fig. 3. Mean serum chloramphenicol concentration after a single intramuscular or intravenous injection of several products in a cross-over study involving 4 goats. Similar findings were reported by others 1, 2, 7, 8, 9, 10 and were considered to result from the entero-hepatic circulation of chloramphenicol. The distribution volume of chloramphenicol in ruminants is large, i.e. approaching total body volume (7, 11, 12, 13). Antibiotics with similar kinetic properties are expected to produce tissue drug concentrations/ serum drug concentration ratios close to unity (6). Indeed similar ratios were found in ruminants (6, 7) after the drug was assayed chemically, but when assays were conducted microbiologically (6) muscle meat/ serum drug concentration ratios were consistently < 1.0. From these earlier works and from the data presented in this report it can be concluded that in order to reach tissue le-. vels of microbiologically-active chloramphenicol of about 5.0 g/ ml and to maintain them for a few hours, a dose of at least 50 mg/ kg to be administered i.m. at two sites are essential prerequisits for chloramphenicol therapy in ruminants. ACK NOW LE DG E M ENTS The technical assistance of A. Smolders, A. van Dinteren, and J. Lette in the conduct of the bioassays is gratefully acknowledged. Thanks are due to Dr. W. J. I. v. d. Gulden, Centraal Dierenlaboratorium, Nijmegen, and Hendrix IW, Druten for providing the sheep and goats, and dairy cows, respectively. I. 2. 3. REFERENCES Corte-Baeten, K. de, Debackere, M.: Chloramphenicol plasma levels in horses, cattle and sheep after oral and intramuscular administration. Zhl. Vet. Med., A. 22, 704-712, (1975). Davis, L. E., Neff, C. A., Baggot, J. D., Powers, T. E.: Pharmacokinctics of chloramphenicol in domestic animals. Am. J. Vet. Res., 33, 2259-2266, (1972). Fabiansson, S., Nillson, T., Bäckstrom, J.: Tissue concentrations of chloramphenicol after intra- THE VETERINARY QUARTERLY. Vol I. No. 1, JAN.1979 57

Downloaded by [37.44.207.8] at 12:51 20 November 2017 muscular injection in pigs. J. Sci. Fd. Agric., 27, 1156-1162 (1976). 4. Glazko, A. J.: Identification of chloramphenicol metabolites and some factors affecting metabolic disposition. Antimicr. Agents & Chemother., (1966), 655-665, (1967). 5. Nouws, J. F. M.: Tissue distribution and residues of some antimicrobial drugs in normal and emergency-slaughtered ruminants. Thesis, State University of Utrecht, 1978. 6. Nouws, J. F. M., Ziv, G. A.: A study of chloramphenicol distribution and residues in normal and emergency-slaughtered cows. Tijdschr. Diergeneesk., 103, 725-735, (1978). 7. Pilloud, M.: Pharmacokinetics, plasma protein binding and dosage of chloramphenicol in cattle and horses. Res. Vet. Sci., 15, 231-238, (1973). 8. Sisodia, C. S., Gupta, V. S., Dunlop, R. H. and Radostits, 0. M.: Chloramphenicol concentrations in blood and milk of cows following parenteral administration. Can. Vet. J., 14, 217-220, (1973). 9. Sisodia, C. S., Dunlop, R. H., Gupta, V. S. and Taksas, L. A.: A pharmacologic study of chloramphenicol in cattle. Am. J. Vet. Res., 34, 1147-1151, (1973). 10. Ziv, G., Bogin, E. and Sulman, F. G.: Blood and milk levels of chloramphenicol in normal and mastitic cows and ewes after intramuscularadministration of chloramphenicol and chloramphenicol succinate. Zbl. Vet. Med., A, 20, 801-811, (1973). I I. Ziv, G., Bogin, E. and Sulman, F. G.: Penetration of radioactive labelled antibiotics from blood into milk in normal and mastitic ewes. Rech. Veter., 5, 15-28, (1974). 12. Ziv, G.: Pharmacokinetic concepts for systemic and intramammary antibiotic treatment in lactating and dry cows. Proc. IDF Seminar on Mastitis Control-1975-Reading, England, pp. 314-340. 13. Ziv, G. and Rasmussen, F.: Distribution of labelled antibiotics in different components of milk following intramammary and intramuscular administration. J. Anim. Sc., 58, 938, (1975). 14. Ziv, G., Nouws, J. F. M., Groothuis, D. G. and Van Miert, A. S. J. P. A. M.: Oral absorption and bioavailability of ampicillin derivatives in calves. Am. J. Vet. Res., 38, 1007-1013, (1977). 58 THE VETERINARY QUARTERLY, VOL. 1. No. I. JAN. 1979