Abstract
The dose-dependent toxicokinetics of enrofloxacin were studied by administering various single subcutaneous doses (5, 10, 20, 40, 70, 100, 150, 200, 300 and 400 mg/kg) in male Sprague-Dawley rats. The blood samples were collected from the tail veins, and the plasma concentration of enrofloxacin was determined by an HPLC-fluorescence detection (FLD) method. The time-concentration profiles of enrofloxacin were well fitted by an one-compartmental model with first order elimination. The absorption half-lives (t1/2abs) ranged from 0.2–0.8 h, and the mean time to maximum plasma concentration (Tmax) ranged from 0.6–1.8 h. On the other hand, marked disproportionate increases of the area under the curve (AUC) and elimination half-lives (t1/2) were observed from the increase of the doses. This result indicates that the elimination of enrofloxacin has nonlinear pharmacokinetic properties with increasing doses. Therefore, we need to take into consideration the possible occurrence of side effects resulting from greater systemic exposure from high dose therapies.
Similar content being viewed by others
References
Alvarez, A. I., Perez, M., Prieto, J. G., Molina, A. J., Real, R., and Merino, G., Fluoroquinolone efflux mediated by ABC transporters. J. Pharm. Sci., 97, 3483–3493 (2008).
Anadon, A., Martinez-Larranaga, M. R., Diaz, M. J., Bringas, P., Martinez, M. A., Fernandez-Cruz, M. L., Fernandez, M. C., and Fernandez, R., Pharmacokinetics and residues of enrofloxacin in chickens. Am. J. Vet. Res., 56, 501–506 (1995).
Aramayona, J. J., Mora, J., Fraile, L. J., Garcia, M. A., Abadia, A. R., and Bregante, M. A., Penetration of enrofloxacin and ciprofloxacin into breast milk, and pharmacokinetics of the drugs in lactating rabbits and neonatal offspring. Am. J. Vet. Res., 57, 547–553 (1996).
Bergan, T., Dalhoff, A., and Rohwedder, R., Pharmacokinetics of ciprofloxacin. Infection, 16Suppl 1, S3–S13 (1988).
Cuzzolin, L. and Fanos, V., Safety of fluoroquinolones in paediatrics. Expert Opin. Drug Saf., 1, 319–324 (2002).
Davis, J. L., Foster, D. M., and Papich, M. G., Pharmacokinetics and tissue distribution of enrofloxacin and its active metabolite ciprofloxacin in calves. J. Vet. Pharmacol. Ther., 30, 564–571 (2007).
Ford, M. M., Dubielzig, R. R., Giuliano, E. A., Moore, C. P., and Narfstrom, K. L., Ocular and systemic manifestations after oral administration of a high dose of enrofloxacin in cats. Am. J. Vet. Res., 68, 190–202 (2007).
Fraile, L. J., Martinez, C., Aramayona, J. J., Abadia, A. R., Bregante, M. A., and Garcia, M. A., Limited capacity of neonatal rabbits to eliminate enrofloxacin and ciprofloxacin. Vet. Q., 19, 162–167 (1997).
Gelatt, K. N., van der Woerdt, A., Ketring, K. L., Andrew, S. E., Brooks, D. E., Biros, D. J., Denis, H. M., and Cutler, T. J., Enrofloxacin-associated retinal degeneration in cats. Vet. Ophthalmol., 4, 99–106 (2001).
Heinen, E., Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single oral administration. J. Vet. Pharmacol. Ther., 25, 1–5 (2002).
Hu, Y., Sampson, K. E., Heyde, B. R., Mandrell, K. M., Li, N., Zutshi, A., and Lai, Y., Saturation of multidrug-resistant protein 2 (mrp2/abcc2)-mediated hepatobiliary secretion: nonlinear pharmacokinetics of a heterocyclic compound in rats after intravenous bolus administration. Drug Metab. Dispos., 37, 841–846 (2009).
Intorre, L., Mengozzi, G., Bertini, S., Bagliacca, M., Luchetti, E., and Soldani, G., The plasma kinetics and tissue distribution of enrofloxacin and its metabolite ciprofloxacin in the Muscovy duck. Vet. Res. Commun., 21, 127–136 (1997).
Jameson, M. B., Baguley, B. C., Kestell, P., Zhao, L., Paxton, J. W., Thompson, P. I., and Waller, S., Pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (AS1404), a novel vascular disrupting agent, in phase I clinical trial. Cancer Chemother. Pharmacol., 59, 681–687 (2007).
Kaartinen, L., Panu, S., and Pyorala, S., Pharmacokinetics of enrofloxacin in horses after single intravenous and intramuscular administration. Equine Vet. J., 29, 378–381 (1997).
Ludden, T. M., Nonlinear pharmacokinetics: clinical Implications. Clin. Pharmacokinet., 20, 429–446 (1991).
Martinez, M., McDermott, P., and Walker, R., Pharmacology of the fluoroquinolones: a perspective for the use in domestic animals. Vet. J., 172, 10–28 (2006).
Pulido, M. M., Molina, A. J., Merino, G., Mendoza, G., Prieto, J. G., and Alvarez, A. I., Interaction of enrofloxacin with breast cancer resistance protein (BCRP/ABCG2): influence of flavonoids and role in milk secretion in sheep. J. Vet. Pharmacol. Ther., 29, 279–287 (2006).
Ramsey, J. C., Nonlinear pharmacokinetics relative to toxicity and use of toxicological data. Drug Metab. Rev., 13, 779–797 (1982).
Rao, G. S., Ramesh, S., Ahmad, A. H., Tripathi, H. C., Sharma, L. D., and Malik, J. K., Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intramuscular administration of enrofloxacin in goats. Vet. Res. Commun., 25, 197–204 (2001).
Rost, K. L. and Roots, I., Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19. Hepatology, 23, 1491–1497 (1996).
Schroder, J., Enrofloxacin: a new antimicrobial agent. J. S. Afr. Vet. Assoc., 60, 122–124 (1989).
Sharma, P. K., Ahmad, A. H., Sharma, L. D., and Varma, R., Pharmacokinetics of enrofloxacin and the rate of formation of its metabolite ciprofloxacin following intravenous and intramuscular single dose administration to male buffalo calves. Vet. J., 166, 101–104 (2003).
Soliman, G. A., Tissue distribution and disposition kinetics of enrofloxacin in healthy and E. coli infected broilers. Dtsch. Tierarztl. Wochenschr., 107, 23–27 (2000).
Stahlmann, R. and Lode, H., Toxicity of quinolones. Drugs, 58Suppl 2, 37–42 (1999).
Tyczkowska, K., Hedeen, K. M., Aucoin, D. P., and Aronson, A. L., High-performance liquid chromatographic method for the simultaneous determination of enrofloxacin and its primary metabolite ciprofloxacin in canine serum and prostatic tissue. J. Chromatogr., 493, 337–346 (1989).
Vaccaro, E., Giorgi, M., Longo, V., Mengozzi, G., and Gervasi, P. G., Inhibition of cytochrome p450 enzymes by enrofloxacin in the sea bass (Dicentrarchus labrax). Aquat. Toxicol., 62, 27–33 (2003).
Vancutsem, P. M. and Babish, J. G., In vitro and in vivo study of the effects of enrofloxacin on hepatic cytochrome P-450. Potential for drug interactions. Vet. Hum. Toxicol., 38, 254–259 (1996).
Vancutsem, P. M., Babish, J. G., and Schwark, W. S., The fluoroquinolone antimicrobials: structure, antimicrobial activity, pharmacokinetics, clinical use in domestic animals and toxicity. Cornell Vet., 80, 173–186 (1990).
Wiuff, C., Lykkesfeldt, J., Aarestrup, F. M., and Svendsen, O., Distribution of enrofloxacin in intestinal tissue and contents of healthy pigs after oral and intramuscular administrations. J. Vet. Pharmacol. Ther., 25, 335–342 (2002).
Wolfson, J. S. and Hooper, D. C., The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob. Agents Chemother., 28, 581–586 (1985).
Wu, G., Meng, Y., Zhu, X., and Huang, C., Pharmacokinetics and tissue distribution of enrofloxacin and its metabolite ciprofloxacin in the Chinese mitten-handed crab, Eriocheir sinensis. Anal. Biochem., 358, 25–30 (2006).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yi, H., Shin, MJ., Cho, SM. et al. Nonlinear toxicokinetics of enrofloxacin in rats. Arch. Pharm. Res. 33, 1851–1857 (2010). https://doi.org/10.1007/s12272-010-1118-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-010-1118-0