Trop Anim Health Prod DOI 10.1007/s11250-014-0595-4
SHORT COMMUNICATIONS
Pharmacokinetics of lincomycin following single intravenous administration in buffalo calves Sreedharan Sreeshitha Gouri & Dinakaran Venkatachalam & Vinod Kumar Dumka
Accepted: 17 April 2014 # Springer Science+Business Media Dordrecht 2014
Abstract Lincomycin 10 mg kg−1, IV in buffalo calves followed two-compartment open model with high distribution rate constant α (11.2±0.42 h−1) and K12/K21 ratio (4.40± 0.10). Distribution half-life was 0.06±0.01 h and AUC was 41.6±1.73 μg mL−1 h. Large Vdarea (1.15±0.03 L kg−1) indicated good distribution of lincomycin in various body fluids and tissues. Peak plasma level of lincomycin (71.8 ± 1.83 μg mL−1) was observed at 1 min as expected by IV route. The elimination half-life and MRT of lincomycin were short (3.30±0.08 and 4.32± 0.11 h, respectively). Lincomycin 10 mg kg−1 IV at 12-h interval would be sufficient to maintain T>MIC above 60 % for bacteria with minimum inhibitory concentrations (MIC) values ≤1.6 μg mL−1. Favourable pharmacokinetic profile in buffalo calves and a convenient dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin. Keywords Buffalo calves . Intravenous . Lincomycin . Pharmacokinetics
Introduction Lincomycin is recommended in dogs and cats for the treatment of gram-positive aerobic and anaerobic S. Sreeshitha Gouri : D. Venkatachalam : V. K. Dumka Department of Veterinary Pharmacology and Toxicology, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141004, India V. K. Dumka (*) Department of Pharmacology and Toxicology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141004, India e-mail: [email protected]
infections, especially against penicillin-resistant strains of Staphylococcus spp. and Streptococcus spp. (Giguere 2006; Papich and Riviere 2009). It has been suggested for potential use in cattle in combination with other antibiotics for susceptible infections that may involve aerobes resistant to the more commonly used medications or anaerobes, including Bacteroides fragilis (USP 2008). It is recommended in domestic animals as an alternative to other antibiotics (Collignon et al. 2008) and has been used for the treatment of respiratory tract infections in sheep, goats and calves (Papich and Riviere 2009). Lincomycin has the ability to penetrate tissues of poor vascularity; it is also effective in the presence of pus and has shown positive response in cattle, sheep and horses (Plenderleith 1988). The main clinical indications of lincomycin are acute and chronic respiratory tract infection, sinusitis, skin, soft tissue, bone and joint infections, septicemia and endocarditis. Successful treatment of arthritis and pedal osteomyelitis u s u a l l y a s s o c i a t e d w i t h Tr u e p e re l l a p y o g e n e s (Arcanobacterium pyogenes) has been reported with lincomycin in sheep (Giguère 2013). Minimum inhibitory concentrations (MIC90) of lincomycin have been reported as 0.06–2.0 μg mL−1 against Streptococcus, Mycoplasma hyopneumoniae, Staphylococcus, T, pyogenes and Mycoplasma spp. (Petinaki et al. 2008; Albarellos et al. 2012; DEFRA 2013; Giguère 2013). Pharmacokinetics of lincomycin is reported in dairy cattle (Weber et al. 1981), calves (Burrows et al. 1983, 1986), pigs (Chaleva and Nquyen 1987), goats (Abo el-sooud et al. 2004) and cats (Albarellos et al. 2012). However, there is no such information available for buffalo species. So this study was undertaken to investigate the pharmacokinetics of lincomycin following single intravenous (IV) administration in buffalo calves.
Trop Anim Health Prod
Materials and methods Experiments were performed on five healthy male buffalo calves (110–140 kg body weight, 6–12 months age). Experimental protocol followed ethical guidelines on the proper care and use of animals and was approved by the Institutional Animal Ethics Committee. Lincomycin was administered IV at single dose of 10 mg kg−1 body weight. Blood samples (3– 4 mL) were collected at 0, 1, 2.5, 5, 10, 15, 30 and 45 min and 1, 1.5, 2, 4, 6, 8, 12 and 24 h and plasma was separated by centrifugation at 1,300g for 15 min. The drug was estimated by HPLC (Perkin Elmer, series 200) using the method of Nielsen and Gyrd-Hansen (1998) by reverse-phase chromatography with analytical C18 column (particle size 5 μ, 4.6× 150 mm, Waters, USA), acetonitrile as mobile phase A (25 %), phosphate buffer as mobile phase B (75 %), flow rate of 1 mL min−1, UV/VIS detector set at 204 nm and Total Chrome software (version 6.1) for instrument control and data analysis. Retention time of lincomycin was 6.9 min and calibration curve was linear between 0.5 and 100 μg mL−1 (r=0.998, data not presented). The limits of detection and quantification were 0.2 and 0.5 μg mL−1, respectively. Extraction recoveries of lincomycin from plasma were 84.0± 4.56, 90.7±4.12 and 94.9±3.29 % for the low, medium and high QC samples, respectively. Accuracy and precision were evaluated with QC samples at concentrations of 0.5, 5 and
25 μg mL−1. Intra- and inter-day assay precision levels were lower than 5 and 6 %, respectively. Appropriate pharmacokinetic model was determined by visual examination of individual concentration time curves and by application of Akaike’s Information Criterion (AIC). The mean pharmacokinetic variables were obtained by averaging the variables for drug disposition from individual animals.
Results and discussion The plasma disposition of lincomycin followed twocompartment open model (Fig. 1) similar to the disposition pattern described for another related antibacterial drug, tylsoin, after IV administration in sheep and goats (Taha et al. 1999). Lincomycin was rapidly transferred from central to peripheral compartment in buffalo calves (Table 1) as is evident from the short distribution half-life which was lesser than the distribution half-life of tylosin in sheep (8.58 min) and goats (12.76 min) after intravenous injection (Taha et al. 1999). Excellent distribution of lincomycin from central to peripheral compartment was evident from the high ratios of K12/K21 and P/C. Ratio of drug concentration between peripheral and central compartments (P/C) was calculated from the equation: P/C=1/fc−1 where, fc, the fraction of administered dose present in the central compartment=β/Kel (Gibaldi and
100
A=44.1
10 Plasma concentration (µg/ml)
B=7.88
β=0.21h-1
1
α=11.2 h-1
0.1 0
2
4
6
8
10
12
14
Time (h)
Fig. 1 Plasma concentration time profile of lincomycin in buffalo calves (n=5) following single IV dose of 10 mg kg−1. Distribution (line–circle–line) and elimination (dotted lines) phases are represented by least square regression lines. Plasma concentration at different time intervals are represented by dots
Trop Anim Health Prod Table 1 Pharmacokinetic parameters of lincomycin following its single intravenous injection (10 mg kg−1) in buffalo calves
Parameter
Unit
Animal number 1
2
Mean±SE 3
4
5
A
μg mL−1
44.8
49.9
38.2
46.3
41.2
44.1±2.03
t½α K12/K21 AUC AUMC Vdarea Vdss P/C Cp0 t½β t½kel ClB VC MRT
h Ratio μg mL−1 h μg mL−1 h2 L kg−1 L kg−1 Ratio μg mL−1 h h L kg−1 h−1 L kg−1 h
0.06 4.42 40.8 171 1.14 1.03 5.01 52.7 3.22 0.540 0.245 0.189 4.20
0.06 4.63 47.3 215 1.05 0.96 5.15 58.6 3.45 0.560 0.171 0.170 4.55
0.06 4.11 41.1 188 1.21 1.11 4.57 45.7 3.50 0.622 0.219 0.218 4.60
0.07 4.52 42.0 180 1.15 1.02 5.21 54.0 3.35 0.540 0.185 0.185 4.30
0.06 4.28 36.5 144 1.20 1.08 4.82 48.8 3.03 0.52 0.205 0.205 3.96
0.06±0.01 4.40±0.10 41.6±1.73 180±11.5 1.15±0.03 1.04±0.03 4.95±0.12 51.9±2.21 3.30±0.08 0.55±0.02 0.24±0.01 0.20±0.01 4.32±0.11
Perrier 1982). Large Vdarea and Vdss indicated good distribution of lincomycin in various body fluids and tissues. Lipophilic nature and high pKa values of 7.6 of this compound might be the major reasons for the good distribution of lincomycin to the tissues. Similar values for Vdarea of lincomycin were also observed in healthy and pneumonic calves (1– 1.3 L kg−1) following IV administration (Burrows et al. 1983, 1986). Total body clearance of lincomycin (0.24± 0.01 L kg−1 h−1), which represents the sum of metabolic and excretory process in buffalo calves, was less than the corresponding values of Cl B reported in calves (0.234 to 0.486 L kg−1 h−1; 3.9 to 8.1 mL min−1 kg−1) and pigs (0.46 L kg−1 h−1) for lincomycin (Burrows et al. 1986; Huimin et al. 2012). Elimination half-life of lincomycin in the present study was 3.30±0.08 h indicating rapid elimination of the drug following IV administration, which was comparable with the t1/2β of 3.38 h in pigs and 2–3 h in calves (Burrows et al. 1983, 1986; Huimin et al. 2012). Lincomycin acts as a time-dependent bacteriostatic drug. The most important pharmacodynamic/pharmacokinetic parameter for this type of drug is the length of time during which the drug remains above the MIC90 value. It is generally recommended that T>MIC should be at least 50 % of the dosage interval to ensure an optimal bactericidal effect (Toutain and Lees 2004). Table 2 shows the calculated percentage of T>MIC (Turnidge 1998) for lincomycin based on the estimated pharmacokinetic parameters obtained following IV injection in buffalo calves for 8, 12 and 24 h dosing interval. The experimental data showed that lincomycin at a dose of 10 mg kg−1 body weight at 12 h interval is sufficient to maintain T>MIC above 60 % following IV injection for bacteria with MIC values ≤1.6 μg mL−1. Although low sensitivity of the analytical method is a weakness of the study, this dosage regimen meets
the pharmacokinetic–pharmacodynamic criteria predicting a successful therapy for susceptible bacteria with MIC ≤1.6 μg mL−1. However, for pathogens having MIC value between 1.6 and 3.2 μg mL−1 more frequent dosing interval of 8 h would be required for desired clinical outcome. Although maximum residue limits (MRLs) or withdrawal times of lincomycin have not been reported for buffaloes in literature, lincomycin has been shown to leave very small amounts of drug residues in the tissues of food animals (Fougeres et al. 2000). There is report that following repeated intramuscular injection of 5 mg lincomycin for 5 days in veal calves the residues in fat and liver tissue were low (Fougeres et al. 2000). The favourable pharmacokinetic profile of lincomycin in buffalo calves with rapid distribution, high AUC, large Vdarea and 12-h dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin. However, lincomycin used in buffalos has to comply with the respect of MRL and withdrawal times to assure the safety of food of animal origin. Table 2 Calculated %T>MIC for lincomycin based on the estimated pharmacokinetic parameters obtained following IV injection 10 mg/kg body weight in buffalo calves for 8, 12 and 24 h dosing interval MIC (μg/mL)
0.2 0.8 1.6 3.2
%T>MIC 24
12
8
74 47 33 19
149 94 67 39
224 141 100 59
Trop Anim Health Prod Acknowledgments The financial support provided by University Grants Commission, New Delhi to conduct this study is thankfully acknowledged. Conflict of interest None of the authors has any financial or personal relationships with other people or organizations that could inappropriately influence or bias the content of the paper.
References Abo El-Sooud, K., Goudah, A. and Abd El-Aty, A.M., 2004. Lack of pharmacokinetic interaction between lincomycin and aspirin in healthy goats, Journal of Veterinary Pharmacology and Therapeutics, 27, 389–392. Albarellos, G.A., Montoya, L., Denamiel, G.A.A., Velo, M.C. and Landoni, M.F., 2012. Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats, Journal of Veterinary Pharmacology and Therapeutics, 35, 534–540. Burrows, G.E., Barto, P.B., Martin, B. and Tripp, M.L., 1983. Comparative pharmacokinetics of antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin, American Journal of Veterinary Research, 44, 1053–1057. Burrows, G.E., Barto, P.B. and Weeks, B.R., 1986. Chloramphenicol, lincomycin and oxytetracycline disposition in calves with experimental pneumonic pasteurellosis. Journal of Veterinary Pharmacology and Therapeutics, 9, 213–222. Chaleva, E. and Nquyen, D.L., 1987. Pharmacokinetic research on Pharmachem’s lincomycin hydrochloride in pigs, Veterinarno Meditsinski Nauki, 24, 47–51. Collignon, P., Courvalin, P. and Aidara-Kane, A. (eds.), 2008. Clinical importance of antimicrobial drugs in human health, In: Guide to Antimicrobial Use in Animals, (Blackwell Publishing, UK), 44–58. DEFRA. 2013. Summary of product characteristics. Department for Environment, Food and Rural Affairs. UK www.vmd.defra.gov. uk/productinformationdatabase/…/SPC_305925.do Fougeres, B.R., Puwaly, J.Z. and MacNell, J., 2000. Lincomycin First Draft. In: Residues of Some Veterinary Drugs in Animals and Foods: Joint FAO/WHO Expert Committee on Food Additives, Monographs. 13, 58–74.
Gibaldi, M. and Perrier, D. (eds.), 1982. Pharmacokinetics, 2nd Edn, (Marcel and Dekker Inc, New York). Giguere, S. (ed.), 2006. Lincosamides, pleuromutilins, and Streptogramins, Antimicrobial Therapy in Veterinary Medicine, 4th Edn, (Blackwell Pub., Ames, USA). Giguère, S., 2013. Lincosamides, pleuromutilins and streptogramins. In: Giguère, S., Prescott, J.F. and Dowling, P.M. (Eds.) Antimicrobial Therapy in Veterinary Medicine. 5th Edn, (John Wiley, Ames, USA). Huimin, L., Ji-An, L.I. and Jin-Gang, N. I. U., 2012. Application of flow feeding technology to lincomycin fermentation, Chinese Journal of Pharmaceuticals, 43, 739–742 Nielsen, P. and Gyrd-Hansen, N., 1998. Bioavailability of spiramycin and lincomycin after oral administration to fed and fasted pigs, Journal of Veterinary Pharmacology and Therapeutics, 21, 251–256. Papich, M.G. and Riviere, J.E. (Eds.), 2009. Chloramphenicol and derivatives, macrolides, lincosamides, and miscellaneous antimicrobials, Veterinary Pharmacology & Therapeutics, 9th edn, (Blackwell Publishing., UK), 963–965. Petinaki, E., Guérin-Faublée, V., Pichereau, V., Villers, C., Achard, A., Malbruny, B. and Leclercq, R. 2008. Lincomycin resistance gene lnu(D) in Streptococcus uberis, Antimicrobial Agents and Chemotherapy. 52(2), 626–630. Plenderleith, R.W., 1988. Treatment of cattle, sheep and horses with lincomycin: case studies. Veterinary Record, 122(5), 112–113. Taha, A.A., Elsheikh, H.A., Khalafalla, A.E., Osman, I.A.M. and Salam abdullah A., (1999) Disposition kinetics of tylosin administered intravenously and intramuscularly in desert sheep and nubian goats. The Veterinary Journal, 158, 210–215. Toutain, P.L. and Lees, P., 2004. Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine, Journal of Veterinary Pharmacology and Therapeutics, 27, 467–477. Turnidge, J.D., 1998. The pharmacdynamics of beta-lactams. Clinical Infectious Diseases, 27, 10–22. USP., 2008. Lincosamides (Veterinary Systemic). The United States Pharmacopeial Convention. Weber, D.J., Barbiers, A.R. and Lallinger, A.J. 1981. Pharmacokinetics of lincomycin in bovine following intravenous and intramammary doses of lincocin. Upjohn Tehnical report.
SHORT COMMUNICATIONS
Pharmacokinetics of lincomycin following single intravenous administration in buffalo calves Sreedharan Sreeshitha Gouri & Dinakaran Venkatachalam & Vinod Kumar Dumka
Accepted: 17 April 2014 # Springer Science+Business Media Dordrecht 2014
Abstract Lincomycin 10 mg kg−1, IV in buffalo calves followed two-compartment open model with high distribution rate constant α (11.2±0.42 h−1) and K12/K21 ratio (4.40± 0.10). Distribution half-life was 0.06±0.01 h and AUC was 41.6±1.73 μg mL−1 h. Large Vdarea (1.15±0.03 L kg−1) indicated good distribution of lincomycin in various body fluids and tissues. Peak plasma level of lincomycin (71.8 ± 1.83 μg mL−1) was observed at 1 min as expected by IV route. The elimination half-life and MRT of lincomycin were short (3.30±0.08 and 4.32± 0.11 h, respectively). Lincomycin 10 mg kg−1 IV at 12-h interval would be sufficient to maintain T>MIC above 60 % for bacteria with minimum inhibitory concentrations (MIC) values ≤1.6 μg mL−1. Favourable pharmacokinetic profile in buffalo calves and a convenient dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin. Keywords Buffalo calves . Intravenous . Lincomycin . Pharmacokinetics
Introduction Lincomycin is recommended in dogs and cats for the treatment of gram-positive aerobic and anaerobic S. Sreeshitha Gouri : D. Venkatachalam : V. K. Dumka Department of Veterinary Pharmacology and Toxicology, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141004, India V. K. Dumka (*) Department of Pharmacology and Toxicology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141004, India e-mail: [email protected]
infections, especially against penicillin-resistant strains of Staphylococcus spp. and Streptococcus spp. (Giguere 2006; Papich and Riviere 2009). It has been suggested for potential use in cattle in combination with other antibiotics for susceptible infections that may involve aerobes resistant to the more commonly used medications or anaerobes, including Bacteroides fragilis (USP 2008). It is recommended in domestic animals as an alternative to other antibiotics (Collignon et al. 2008) and has been used for the treatment of respiratory tract infections in sheep, goats and calves (Papich and Riviere 2009). Lincomycin has the ability to penetrate tissues of poor vascularity; it is also effective in the presence of pus and has shown positive response in cattle, sheep and horses (Plenderleith 1988). The main clinical indications of lincomycin are acute and chronic respiratory tract infection, sinusitis, skin, soft tissue, bone and joint infections, septicemia and endocarditis. Successful treatment of arthritis and pedal osteomyelitis u s u a l l y a s s o c i a t e d w i t h Tr u e p e re l l a p y o g e n e s (Arcanobacterium pyogenes) has been reported with lincomycin in sheep (Giguère 2013). Minimum inhibitory concentrations (MIC90) of lincomycin have been reported as 0.06–2.0 μg mL−1 against Streptococcus, Mycoplasma hyopneumoniae, Staphylococcus, T, pyogenes and Mycoplasma spp. (Petinaki et al. 2008; Albarellos et al. 2012; DEFRA 2013; Giguère 2013). Pharmacokinetics of lincomycin is reported in dairy cattle (Weber et al. 1981), calves (Burrows et al. 1983, 1986), pigs (Chaleva and Nquyen 1987), goats (Abo el-sooud et al. 2004) and cats (Albarellos et al. 2012). However, there is no such information available for buffalo species. So this study was undertaken to investigate the pharmacokinetics of lincomycin following single intravenous (IV) administration in buffalo calves.
Trop Anim Health Prod
Materials and methods Experiments were performed on five healthy male buffalo calves (110–140 kg body weight, 6–12 months age). Experimental protocol followed ethical guidelines on the proper care and use of animals and was approved by the Institutional Animal Ethics Committee. Lincomycin was administered IV at single dose of 10 mg kg−1 body weight. Blood samples (3– 4 mL) were collected at 0, 1, 2.5, 5, 10, 15, 30 and 45 min and 1, 1.5, 2, 4, 6, 8, 12 and 24 h and plasma was separated by centrifugation at 1,300g for 15 min. The drug was estimated by HPLC (Perkin Elmer, series 200) using the method of Nielsen and Gyrd-Hansen (1998) by reverse-phase chromatography with analytical C18 column (particle size 5 μ, 4.6× 150 mm, Waters, USA), acetonitrile as mobile phase A (25 %), phosphate buffer as mobile phase B (75 %), flow rate of 1 mL min−1, UV/VIS detector set at 204 nm and Total Chrome software (version 6.1) for instrument control and data analysis. Retention time of lincomycin was 6.9 min and calibration curve was linear between 0.5 and 100 μg mL−1 (r=0.998, data not presented). The limits of detection and quantification were 0.2 and 0.5 μg mL−1, respectively. Extraction recoveries of lincomycin from plasma were 84.0± 4.56, 90.7±4.12 and 94.9±3.29 % for the low, medium and high QC samples, respectively. Accuracy and precision were evaluated with QC samples at concentrations of 0.5, 5 and
25 μg mL−1. Intra- and inter-day assay precision levels were lower than 5 and 6 %, respectively. Appropriate pharmacokinetic model was determined by visual examination of individual concentration time curves and by application of Akaike’s Information Criterion (AIC). The mean pharmacokinetic variables were obtained by averaging the variables for drug disposition from individual animals.
Results and discussion The plasma disposition of lincomycin followed twocompartment open model (Fig. 1) similar to the disposition pattern described for another related antibacterial drug, tylsoin, after IV administration in sheep and goats (Taha et al. 1999). Lincomycin was rapidly transferred from central to peripheral compartment in buffalo calves (Table 1) as is evident from the short distribution half-life which was lesser than the distribution half-life of tylosin in sheep (8.58 min) and goats (12.76 min) after intravenous injection (Taha et al. 1999). Excellent distribution of lincomycin from central to peripheral compartment was evident from the high ratios of K12/K21 and P/C. Ratio of drug concentration between peripheral and central compartments (P/C) was calculated from the equation: P/C=1/fc−1 where, fc, the fraction of administered dose present in the central compartment=β/Kel (Gibaldi and
100
A=44.1
10 Plasma concentration (µg/ml)
B=7.88
β=0.21h-1
1
α=11.2 h-1
0.1 0
2
4
6
8
10
12
14
Time (h)
Fig. 1 Plasma concentration time profile of lincomycin in buffalo calves (n=5) following single IV dose of 10 mg kg−1. Distribution (line–circle–line) and elimination (dotted lines) phases are represented by least square regression lines. Plasma concentration at different time intervals are represented by dots
Trop Anim Health Prod Table 1 Pharmacokinetic parameters of lincomycin following its single intravenous injection (10 mg kg−1) in buffalo calves
Parameter
Unit
Animal number 1
2
Mean±SE 3
4
5
A
μg mL−1
44.8
49.9
38.2
46.3
41.2
44.1±2.03
t½α K12/K21 AUC AUMC Vdarea Vdss P/C Cp0 t½β t½kel ClB VC MRT
h Ratio μg mL−1 h μg mL−1 h2 L kg−1 L kg−1 Ratio μg mL−1 h h L kg−1 h−1 L kg−1 h
0.06 4.42 40.8 171 1.14 1.03 5.01 52.7 3.22 0.540 0.245 0.189 4.20
0.06 4.63 47.3 215 1.05 0.96 5.15 58.6 3.45 0.560 0.171 0.170 4.55
0.06 4.11 41.1 188 1.21 1.11 4.57 45.7 3.50 0.622 0.219 0.218 4.60
0.07 4.52 42.0 180 1.15 1.02 5.21 54.0 3.35 0.540 0.185 0.185 4.30
0.06 4.28 36.5 144 1.20 1.08 4.82 48.8 3.03 0.52 0.205 0.205 3.96
0.06±0.01 4.40±0.10 41.6±1.73 180±11.5 1.15±0.03 1.04±0.03 4.95±0.12 51.9±2.21 3.30±0.08 0.55±0.02 0.24±0.01 0.20±0.01 4.32±0.11
Perrier 1982). Large Vdarea and Vdss indicated good distribution of lincomycin in various body fluids and tissues. Lipophilic nature and high pKa values of 7.6 of this compound might be the major reasons for the good distribution of lincomycin to the tissues. Similar values for Vdarea of lincomycin were also observed in healthy and pneumonic calves (1– 1.3 L kg−1) following IV administration (Burrows et al. 1983, 1986). Total body clearance of lincomycin (0.24± 0.01 L kg−1 h−1), which represents the sum of metabolic and excretory process in buffalo calves, was less than the corresponding values of Cl B reported in calves (0.234 to 0.486 L kg−1 h−1; 3.9 to 8.1 mL min−1 kg−1) and pigs (0.46 L kg−1 h−1) for lincomycin (Burrows et al. 1986; Huimin et al. 2012). Elimination half-life of lincomycin in the present study was 3.30±0.08 h indicating rapid elimination of the drug following IV administration, which was comparable with the t1/2β of 3.38 h in pigs and 2–3 h in calves (Burrows et al. 1983, 1986; Huimin et al. 2012). Lincomycin acts as a time-dependent bacteriostatic drug. The most important pharmacodynamic/pharmacokinetic parameter for this type of drug is the length of time during which the drug remains above the MIC90 value. It is generally recommended that T>MIC should be at least 50 % of the dosage interval to ensure an optimal bactericidal effect (Toutain and Lees 2004). Table 2 shows the calculated percentage of T>MIC (Turnidge 1998) for lincomycin based on the estimated pharmacokinetic parameters obtained following IV injection in buffalo calves for 8, 12 and 24 h dosing interval. The experimental data showed that lincomycin at a dose of 10 mg kg−1 body weight at 12 h interval is sufficient to maintain T>MIC above 60 % following IV injection for bacteria with MIC values ≤1.6 μg mL−1. Although low sensitivity of the analytical method is a weakness of the study, this dosage regimen meets
the pharmacokinetic–pharmacodynamic criteria predicting a successful therapy for susceptible bacteria with MIC ≤1.6 μg mL−1. However, for pathogens having MIC value between 1.6 and 3.2 μg mL−1 more frequent dosing interval of 8 h would be required for desired clinical outcome. Although maximum residue limits (MRLs) or withdrawal times of lincomycin have not been reported for buffaloes in literature, lincomycin has been shown to leave very small amounts of drug residues in the tissues of food animals (Fougeres et al. 2000). There is report that following repeated intramuscular injection of 5 mg lincomycin for 5 days in veal calves the residues in fat and liver tissue were low (Fougeres et al. 2000). The favourable pharmacokinetic profile of lincomycin in buffalo calves with rapid distribution, high AUC, large Vdarea and 12-h dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin. However, lincomycin used in buffalos has to comply with the respect of MRL and withdrawal times to assure the safety of food of animal origin. Table 2 Calculated %T>MIC for lincomycin based on the estimated pharmacokinetic parameters obtained following IV injection 10 mg/kg body weight in buffalo calves for 8, 12 and 24 h dosing interval MIC (μg/mL)
0.2 0.8 1.6 3.2
%T>MIC 24
12
8
74 47 33 19
149 94 67 39
224 141 100 59
Trop Anim Health Prod Acknowledgments The financial support provided by University Grants Commission, New Delhi to conduct this study is thankfully acknowledged. Conflict of interest None of the authors has any financial or personal relationships with other people or organizations that could inappropriately influence or bias the content of the paper.
References Abo El-Sooud, K., Goudah, A. and Abd El-Aty, A.M., 2004. Lack of pharmacokinetic interaction between lincomycin and aspirin in healthy goats, Journal of Veterinary Pharmacology and Therapeutics, 27, 389–392. Albarellos, G.A., Montoya, L., Denamiel, G.A.A., Velo, M.C. and Landoni, M.F., 2012. Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats, Journal of Veterinary Pharmacology and Therapeutics, 35, 534–540. Burrows, G.E., Barto, P.B., Martin, B. and Tripp, M.L., 1983. Comparative pharmacokinetics of antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin, American Journal of Veterinary Research, 44, 1053–1057. Burrows, G.E., Barto, P.B. and Weeks, B.R., 1986. Chloramphenicol, lincomycin and oxytetracycline disposition in calves with experimental pneumonic pasteurellosis. Journal of Veterinary Pharmacology and Therapeutics, 9, 213–222. Chaleva, E. and Nquyen, D.L., 1987. Pharmacokinetic research on Pharmachem’s lincomycin hydrochloride in pigs, Veterinarno Meditsinski Nauki, 24, 47–51. Collignon, P., Courvalin, P. and Aidara-Kane, A. (eds.), 2008. Clinical importance of antimicrobial drugs in human health, In: Guide to Antimicrobial Use in Animals, (Blackwell Publishing, UK), 44–58. DEFRA. 2013. Summary of product characteristics. Department for Environment, Food and Rural Affairs. UK www.vmd.defra.gov. uk/productinformationdatabase/…/SPC_305925.do Fougeres, B.R., Puwaly, J.Z. and MacNell, J., 2000. Lincomycin First Draft. In: Residues of Some Veterinary Drugs in Animals and Foods: Joint FAO/WHO Expert Committee on Food Additives, Monographs. 13, 58–74.
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