Abstract
Background: Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target- age animals.
Objective: To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep.
Methods: The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC–UV and analyzed using a non-compartmental method.
Results: ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t1/2ʎz and Vdss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC0-∞CIP/AUC0-∞ENR ratios were higher in one-month-old than in six- and twelve-months sheep.
Conclusion: The most important pharmacokinetic changes associated with aging in sheep are decreased Vdss and t1/2ʎz of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC0–24/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.
Graphical Abstract
[1]
FAO A.. 2023. Available from:https://www.fao.org/livestock-systems/global-distributions/sheep/en/
[2]
FAO B.. Crops and livestock products. 2023. Available from:https://www.-fao.org/faostat/en/#data/QCL/visualize
[3]
Radostits, O.M.; Gay, C.C.; Hinchcliff, K.W.; Constable, P.D. Veterinary Medicine E-Book: A textbook of the diseases of cattle, horses, sheep, pigs and goats. Elsevier Health Sciences, 2006, 2006, 759-1125.
[4]
Routledge, P.A. Pharmacokinetics in children. J. Antimicrob. Chemother., 1994, 34(Suppl. A), 19-24.
[http://dx.doi.org/10.1093/jac/34.suppl_A.19] [PMID: 7844070]
[http://dx.doi.org/10.1093/jac/34.suppl_A.19] [PMID: 7844070]
[5]
Coskun, D.; Corum, O.; Durna Corum, D.; Cetin, G.; Irmak, M.; Ceyhan, H.R.; Uney, K. Age-related changes in the pharmacokinetics of meloxicam after intravenous administration in sheep. J. Vet. Pharmacol. Ther., 2023, 46(5), 326-331.
[http://dx.doi.org/10.1111/jvp.13404] [PMID: 37488663]
[http://dx.doi.org/10.1111/jvp.13404] [PMID: 37488663]
[6]
Uney, K.; Terzi, E.; Durna Corum, D.; Ozdemir, R.C.; Bilen, S.; Corum, O. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of enrofloxacin following single oral administration of different doses in brown trout (Salmo trutta). Animals, 2021, 11(11), 3086.
[http://dx.doi.org/10.3390/ani11113086] [PMID: 34827818]
[http://dx.doi.org/10.3390/ani11113086] [PMID: 34827818]
[7]
Corum, O.; Altan, F.; Yildiz, R.; Ider, M.; Ok, M.; Uney, K. Pharmacokinetics of enrofloxacin and danofloxacin in premature calves. J. Vet. Pharmacol. Ther., 2019, 42(6), 624-631.
[http://dx.doi.org/10.1111/jvp.12787] [PMID: 31190327]
[http://dx.doi.org/10.1111/jvp.12787] [PMID: 31190327]
[8]
Daundkar, P.S.; Vemu, B.; Dumka, V.K.; Sharma, S.K. Pharmacokinetic-pharmacodynamic integration of enrofloxacin and its metabolite ciprofloxacin in buffalo calves. Vet. Med. Sci., 2015, 1(2), 63-71.
[http://dx.doi.org/10.1002/vms3.10] [PMID: 29067175]
[http://dx.doi.org/10.1002/vms3.10] [PMID: 29067175]
[9]
Trouchon, T.; Lefebvre, S. A review of enrofloxacin for veterinary use. Open J. Vet. Med., 2016, 6(2), 40-58.
[http://dx.doi.org/10.4236/ojvm.2016.62006]
[http://dx.doi.org/10.4236/ojvm.2016.62006]
[10]
Anonymous ENROGAL 100 mg/mL oral solution. 2023. Available from:https://www.pharmagal.sk/en/products/antibiotics-and-chemotherapeutics/enrogal-100-mgml-oral-solution/
[11]
Anonymous Summary of Product Characteristics. 2023. Available from:https://www.hpra.ie/img/uploaded/swedocuments/Licence_VPA10836-005-001_12112019161905.pdf
[13]
Seguin, M.A.; Papich, M.G.; Sigle, K.J.; Gibson, N.M.; Levy, J.K. Pharmacokinetics of enrofloxacin in neonatal kittens. Am. J. Vet. Res., 2004, 65(3), 350-356.
[http://dx.doi.org/10.2460/ajvr.2004.65.350] [PMID: 15027685]
[http://dx.doi.org/10.2460/ajvr.2004.65.350] [PMID: 15027685]
[14]
Kaartinen, L.; PyÖrÄlÄ, S.; Moilanen, M.; RÄisÄnen, S. Pharmacokinetics of enrofloxacin in newborn and one-week-old calves. J. Vet. Pharmacol. Ther., 1997, 20(6), 479-482.
[http://dx.doi.org/10.1046/j.1365-2885.1997.00100.x] [PMID: 9430772]
[http://dx.doi.org/10.1046/j.1365-2885.1997.00100.x] [PMID: 9430772]
[15]
Bermingham, E.C.; Papich, M.G.; Vivrette, S.L. Pharmacokinetics of enrofloxacin administered intravenously and orally to foals. Am. J. Vet. Res., 2000, 61(6), 706-709.
[http://dx.doi.org/10.2460/ajvr.2000.61.706] [PMID: 10850849]
[http://dx.doi.org/10.2460/ajvr.2000.61.706] [PMID: 10850849]
[16]
Poźniak, B.; Tikhomirov, M.; Motykiewicz-Pers, K.; Bobrek, K.; Świtała, M. The influence of age and body weight gain on enrofloxacin pharmacokinetics in turkeys-Allometric approach to dose optimization. J. Vet. Pharmacol. Ther., 2020, 43(1), 67-78.
[http://dx.doi.org/10.1111/jvp.12833] [PMID: 31845357]
[http://dx.doi.org/10.1111/jvp.12833] [PMID: 31845357]
[17]
Fraile, L.J.; Martinez, C.; Aramayona, J.J.; Abadía, A.R.; Bregante, M.A.; García, M.A. Limited capacity of neonatal rabbits to eliminate enrofloxacin and ciprofloxacin. Vet. Q., 1997, 19(4), 162-167.
[http://dx.doi.org/10.1080/01652176.1997.9694764] [PMID: 9413113]
[http://dx.doi.org/10.1080/01652176.1997.9694764] [PMID: 9413113]
[18]
Bermingham, E.C.; Papich, M.G. Pharmacokinetics after intravenous and oral administration of enrofloxacin in sheep. Am. J. Vet. Res., 2002, 63(7), 1012-1017.
[http://dx.doi.org/10.2460/ajvr.2002.63.1012] [PMID: 12118662]
[http://dx.doi.org/10.2460/ajvr.2002.63.1012] [PMID: 12118662]
[19]
Haritova, A.; Lashev, L.; Pashov, D. Pharmacokinetics of enrofloxacin in lactating sheep. Res. Vet. Sci., 2003, 74(3), 241-245.
[http://dx.doi.org/10.1016/S0034-5288(03)00003-1] [PMID: 12726743]
[http://dx.doi.org/10.1016/S0034-5288(03)00003-1] [PMID: 12726743]
[20]
Karademir, U.; Boyacioglu, M.; Kum, C.; Sekkin, S. Comparative pharmacokinetics of enrofloxacin, danofloxacin and marbofloxacin following intramuscular administration in sheep. Small Rumin. Res., 2015, 133, 108-111.
[http://dx.doi.org/10.1016/j.smallrumres.2015.09.007]
[http://dx.doi.org/10.1016/j.smallrumres.2015.09.007]
[21]
Corum, O.; Terzi, E.; Durna Corum, D.; Tastan, Y.; Gonzales, R.C.; Kenanoglu, O.N.; Arriesgado, D.M.; Navarro, V.R.; Bilen, S.; Sonmez, A.Y.; Uney, K. Plasma and muscle tissue disposition of enrofloxacin in Nile tilapia ( Oreochromis niloticus ) after intravascular, intraperitoneal, and oral administrations. Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess., 2022, 39(11), 1806-1817.
[http://dx.doi.org/10.1080/19440049.2022.2121429] [PMID: 36136094]
[http://dx.doi.org/10.1080/19440049.2022.2121429] [PMID: 36136094]
[22]
European Medicines Agency (EMA). Guideline on Bioanalytical Method Validation. Committee for Medicinal Products for Human Use (CHMP). 2011. Available from:https://www.ema.europa.eu/documents/scientific-guideline/guideline- bioanalytical- method -validation_en.pdf
[23]
Orden, J.A.; Ruiz-Santa-Quiteria, J.A.; Cid, D.; Díez, R.; Martínez, S.; de la Fuente, R. Quinolone resistance in potentially pathogenic and non-pathogenic Escherichia coli strains isolated from healthy ruminants. J. Antimicrob. Chemother., 2001, 48(3), 421-424.
[http://dx.doi.org/10.1093/jac/48.3.421] [PMID: 11533010]
[http://dx.doi.org/10.1093/jac/48.3.421] [PMID: 11533010]
[24]
Loria, G.R.; Sammartino, C.; Nicholas, R.A.J.; Ayling, R.D. In vitro susceptibilities of field isolates of Mycoplasma agalactiae to oxytetracycline, tylosin, enrofloxacin, spiramycin and lincomycin–spectinomycin. Res. Vet. Sci., 2003, 75(1), 3-7.
[http://dx.doi.org/10.1016/S0034-5288(03)00030-4] [PMID: 12801456]
[http://dx.doi.org/10.1016/S0034-5288(03)00030-4] [PMID: 12801456]
[25]
Serrano-Rodríguez, J.M.; Cárceles-García, C.; Cárceles-Rodríguez, C.M.; Gabarda, M.L.; Serrano-Caballero, J.M.; Fernández-Varón, E. Susceptibility and PK/PD relationships of Staphylococcus aureus strains isolated from the milk of sheep and goats with clinical mastitis to five veterinary fluoroquinolones. Vet. Rec., 2017, 180(15), 376-376.
[http://dx.doi.org/10.1136/vr.103964] [PMID: 28213532]
[http://dx.doi.org/10.1136/vr.103964] [PMID: 28213532]
[26]
Cid, D.; Fernández-Garayzábal, J.F.; Pinto, C.; Domínguez, L.; Vela, A.I. Antimicrobial susceptibility of Pasteurella multocida isolated from sheep and pigs in Spain – Short communication. Acta Vet. Hung., 2019, 67(4), 489-498.
[http://dx.doi.org/10.1556/004.2019.048] [PMID: 31842595]
[http://dx.doi.org/10.1556/004.2019.048] [PMID: 31842595]
[27]
Pantozzi, F.L.; Ibar, M.P.; Nievas, V.F.; Vigo, G.B.; Moredo, F.A.; Giacoboni, G.I. Wild-type minimal inhibitory concentration distributions in bacteria of animal origin in Argentina. Rev. Argent. Microbiol., 2014, 46(1), 34-40.
[http://dx.doi.org/10.1016/S0325-7541(14)70045-8] [PMID: 24721272]
[http://dx.doi.org/10.1016/S0325-7541(14)70045-8] [PMID: 24721272]
[28]
Maksimović, Z.; Bačić, A.; Rifatbegović, M. Antimicrobial susceptibility of caprine and ovine Mycoplasma ovipneumoniae isolates. Microb. Drug Resist., 2020, 26(10), 1271-1274.
[http://dx.doi.org/10.1089/mdr.2019.0465] [PMID: 32412832]
[http://dx.doi.org/10.1089/mdr.2019.0465] [PMID: 32412832]
[29]
Elsheikh, H.A.; Taha, A.A.W.; Khalafallah, A.I.; Osman, I.A.M. Disposition kinetics of enrofloxacin (Baytril 5%) in sheep and goats following intravenous and intramuscular injection using a microbiological assay. Res. Vet. Sci., 2002, 73(2), 125-129.
[http://dx.doi.org/10.1016/S0034-5288(02)00020-6] [PMID: 12204629]
[http://dx.doi.org/10.1016/S0034-5288(02)00020-6] [PMID: 12204629]
[30]
Coskun, D.; Parlak, K.; Dik, B.; Faki, H.; Bahcivan, E.; Yazar, E.; Er, A. Effect of enrofloxacin on the joint fluid/blood oxidative status and organ damage markers. Annu. Res. Rev. Biol., 2018, 25(3), 1-7.
[http://dx.doi.org/10.9734/ARRB/2018/40537]
[http://dx.doi.org/10.9734/ARRB/2018/40537]
[31]
Khazaeel, K.; Mazaheri, Y.; Hashemi Tabar, M.; Najafzadeh, H.; Morovvati, H.; Ghadrdan, A. Effect of enrofloxacin on histochemistry, immunohistochemistry and molecular changes in lamb articular cartilage. Acta Med. Iran., 2015, 53(9), 555-561.
[PMID: 26553083]
[PMID: 26553083]
[32]
Bregante, M.A.; Saez, P.; Aramayona, J.J.; Fraile, L.; Garcia, M.A.; Solans, C. Comparative pharmacokinetics of enrofloxacin in mice, rats, rabbits, sheep, and cows. Am. J. Vet. Res., 1999, 60(9), 1111-1116.
[PMID: 10490081]
[PMID: 10490081]
[33]
Searle, T.W. Body composition in lambs and young sheep and its prediction in vivo from tritiated water space and body weight. J. Agric. Sci., 1970, 74(2), 357-362.
[http://dx.doi.org/10.1017/S0021859600022991]
[http://dx.doi.org/10.1017/S0021859600022991]
[34]
Uney, K.; Yuksel, M.; Durna Corum, D.; Coskun, D.; Turk, E.; Dingil, H.B.; Corum, O. Effect of xylazine on pharmacokinetics and physiological efficacy of intravenous carprofen in castrated goats kids. Animals, 2023, 13(17), 2700.
[http://dx.doi.org/10.3390/ani13172700] [PMID: 37684964]
[http://dx.doi.org/10.3390/ani13172700] [PMID: 37684964]
[35]
González, F.; Rodríguez, C.; Nieto, J.; De Vicente, M.L.; San Andrés, M.D.; Andrés, M.I.S. Age-related differences in norfloxacin pharmacokinetic behaviour following intravenous and oral administration in sheep. Vet. Q., 1997, 19(4), 145-150.
[http://dx.doi.org/10.1080/01652176.1997.9694760] [PMID: 9413109]
[http://dx.doi.org/10.1080/01652176.1997.9694760] [PMID: 9413109]
[36]
Kaddouri, M.; Larrieu, G.; Eeckhoutte, C.; Galtier, P. The development of drug-metabolizing enzymes in female sheep livers. J. Vet. Pharmacol. Ther., 1990, 13(4), 340-349.
[http://dx.doi.org/10.1111/j.1365-2885.1990.tb00787.x] [PMID: 2287026]
[http://dx.doi.org/10.1111/j.1365-2885.1990.tb00787.x] [PMID: 2287026]
[37]
Sharma, P.C.; Jain, A.; Jain, S. Fluoroquinolone antibacterials: A review on chemistry, microbiology and therapeutic prospects. Acta Pol. Pharm., 2009, 66(6), 587-604.
[PMID: 20050522]
[PMID: 20050522]
[38]
Toutain, P.L.; Bousquet-Mélou, A. Plasma clearance. J. Vet. Pharmacol. Ther., 2004, 27(6), 415-425.
[http://dx.doi.org/10.1111/j.1365-2885.2004.00605.x] [PMID: 15601437]
[http://dx.doi.org/10.1111/j.1365-2885.2004.00605.x] [PMID: 15601437]
[39]
Mengozzi, G.; Intorre, L.; Bertini, S.; Soldani, G. Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and intramuscular administrations in sheep. Am. J. Vet. Res., 1996, 57(7), 1040-1043.
[PMID: 8807018]
[PMID: 8807018]
[40]
Xu, X.; Lu, Q.; Yang, Y.; Martínez, M.A.; Lopez-Torres, B.; Martínez-Larrañaga, M.R.; Wang, X.; Anadón, A.; Ares, I. A proposed “steric-like effect” for the slowdown of enrofloxacin antibiotic metabolism by ciprofloxacin, and its mechanism. Chemosphere, 2021, 284, 131347.
[http://dx.doi.org/10.1016/j.chemosphere.2021.131347] [PMID: 34323809]
[http://dx.doi.org/10.1016/j.chemosphere.2021.131347] [PMID: 34323809]
[41]
Galtier, P.; Alvinerie, M. Pharmacological basis for hepatic drug metabolism in sheep. Vet. Res., 1996, 27(4-5), 363-372.
[PMID: 8822607]
[PMID: 8822607]
[42]
Coskun, D.; Corum, O.; Yazar, E. Effect of supportive therapy on the pharmacokinetics of intravenous marbofloxacin in endotoxemic sheep. J. Vet. Pharmacol. Ther., 2020, 43(3), 288-296.
[http://dx.doi.org/10.1111/jvp.12849] [PMID: 32133667]
[http://dx.doi.org/10.1111/jvp.12849] [PMID: 32133667]
[43]
Durna Corum, D.; Corum, O.; Yildiz, R.; Eser Faki, H.; Ider, M.; Cetin, G.; Uney, K. Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep. Acta Vet. Hung., 2020, 68(1), 65-70.
[http://dx.doi.org/10.1556/004.2020.00015] [PMID: 32384070]
[http://dx.doi.org/10.1556/004.2020.00015] [PMID: 32384070]
[44]
Corum, D.D.; Corum, O.; Altan, F.; Eser Faki, H.; Bahcivan, E.; Er, A.; Uney, K. Pharmacokinetics of ceftriaxone following single ascending intravenous doses in sheep. Small Rumin. Res., 2018, 169, 108-112.
[http://dx.doi.org/10.1016/j.smallrumres.2018.07.019]
[http://dx.doi.org/10.1016/j.smallrumres.2018.07.019]
[45]
Cetin, G.; Durna Corum, D.; Corum, O.; Atik, O.; Coskun, D.; Uney, K. Effect of ketoprofen and tolfenamic acid on intravenous pharmacokinetics of ceftriaxone in sheep. J. Vet. Pharmacol. Ther., 2021, 44(6), 945-951.
[http://dx.doi.org/10.1111/jvp.13001] [PMID: 34312894]
[http://dx.doi.org/10.1111/jvp.13001] [PMID: 34312894]