Ali RASSOULI, Alwan AL QUSHAWI, Fatemeh ATYABI, Seyed Mostafa PEIGHAMBARI, Gholam Reza SHAMS, Mehdi ZOGHİ

Pharmacokinetics and bioavailability of three promising tilmicosin-loaded lipid nanoparticles in comparison with tilmicosin phosphate following oral administrationin broiler chickens

Tilmicosin (TLM) is a semisynthetic antimicrobial agent used mainly in poultry and cattle, but it has relatively poor oral bioavailability. This study was conducted to compare the bioavailability (BA) and main pharmacokinetic (PK) parameters of TLM after oral administration of tilmicosin phosphate (TLM-PH) and three newly prepared lipid nanoparticles (LNPs) of TLM including solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid-core nanocapsules (LNCs). Sixty broiler chickens were divided into eight groups. In four treatment groups (n = 10), each bird was given a single oral dose (20 mg/kg) of a TLM formulation after overnight fasting, and in four control groups (n = 5), the vehicles of those formulations or distilled water were given. Plasma TLM concentrations were analyzed using an HPLC method and the related PK parameters (Cmax, Tmax, AUC0 ∞, t1/2, kel, ClB/F, MRT, and Vd/F) were obtained by noncompartmental analysis. The relative bioavailability of TLM-SLNs, TLM-NLCs, and TLM-LNCs were 1.7, 2.7, and 3.6 times, respectively, more than the BA of TLM-PH. Mean Cmax values were 1.21, 1.58, 1.76, and 2.17 μg/mL for TLM-PH, TLM-SLN, TLM-NLC, and TLM-LNC, respectively. In conclusion, TLM-LNPs improved drug BA and PK parameters, especially the TLM-LNC formulation, which suggests an efficient delivery system for TLM.

PDF

___

1. Abu-Basha EA, Idkaidek NM, Al-Shunnaq AF. Pharmacokinetics of tilmicosin (Provitil powder and Pulmotil liquid AC) oral formulations in chickens. Vet Res Commun 2007; 31: 477-485.
2. Avci T, Elmas M. Milk and blood pharmacokinetics of tylosin and tilmicosin following parenteral administrations to cows. Sci World J 2014; 2014: 869096.
3. Eraslan G. Effects of different doses of tilmicosin on erythrocyte catalase activity and plasma malondialdehyde levels in chicks. Bull Vet Inst Pulawy 2007; 51: 145-147.
4. Jordan FTW, Horrocks BK. The minimum inhibitory concentration of tilmicosin and tylosin for Mycoplasma synoviae and a comparison of their efficacy in the control of Mycoplasma gallisepticum infection in broiler chicks. Avian Dis 1996; 40: 326-334.
5. Chen X, Wang T, Lu M, Zhu L, Wang Y, Zhou W. Preparation and evaluation of tilmicosin-loaded hydrogenated castor oil nanoparticle suspensions of different particle sizes. Int J Nanomed 2014; 9: 2655-2664.
6. Han C, Qi CM, Zhao BK, Cao J, Xie SY, Wang SL, Zhou WZ. Hydrogenated castor oil nanoparticles as carriers for the subcutaneous administration of tilmicosin: in vitro and in vivo studies. J Vet Pharmacol Therap 2008; 32: 116-123.
7. Zhang T, Chen J, Zhang Y, Shen Q, Pan W. Characterization and evaluation of nanostructured lipid carrier as a vehicle for oral delivery of etoposide. Eur J Pharmaceut Sci 2011; 43: 174-179.
8. Plapied L, Duhem N, Des Rieux A, Préat V. Fate of polymeric nanocarriers for oral drug delivery. Curr Opin Colloid Interface Sci 2011; 16: 228-237.
9. Beloqui A, Solinís MA, Gascón AR, Del Pozo-Rodríguez A, Des Rieux A, Préa VT. Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier. J Controlled Release 2013; 166: 115-123.
10. Tiwari R, Pathak K. Nanostructured lipid carrier versus solid lipid nanoparticles of simvastatin: comparative analysis of characteristics, pharmacokinetics and tissue uptake. Int J Pharmaceut 2011; 415: 232-243.
11. Severino P, Andreani T, Macedo AS, Fangueiro JF, Santana MHA, Silva AM, Souto EB. Current state-of-art and new trends on lipid nanoparticles (SLN and NLC) for oral drug delivery. J Drug Delivery 2012; 2012: 750891.
12. Battaglia L, Gallarate M. Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery. Expert Opin Drug Deliv 2012; 9: 497-508.
13. Shah R, Eldrige D, Palombo E, Harding I. Composition and structure. In: Shah R, Eldridge D, Palombo E, Harding I, editors. Lipid Nanoparticles: Production, Characterization and Stability. Berlin, Germany: Springer; 2015. pp. 11-22.
14. Xie S, Zhu L, Dong Z, Wang Y, Wang X, Zhou W. Preparation and evaluation of ofloxacin-loaded palmitic acid solid lipid nanoparticles. Int J Nanomed 2011; 6: 547-555.
15. Zhuanga CY, Li N, Wang M, Zhang XN, Pana WS, Peng JJ, Pana YS, Tang X. Preparation and characterization of vinpocetine loaded nanostructured lipid carriers (NLC) for improved oral bioavailability. Int J Pharmaceut 2010; 394: 179-185.
16. Bender EA, Adorne MD, Colomé LM, Abdalla DSP, Guterres SS, Pohlmann AR. Hemocompatibility of poly(-caprolactone) lipid-core nanocapsules stabilized with polysorbate 80-lecithin and uncoated or coated with chitosan. Int J Pharmaceut 2012; 426: 271-279.
17. Cattania VB, Fiel LA, Jager A, Jager E, Colome LM, Uchoa F. Lipid-core nanocapsules restrained the indomethacin ethyl ester hydrolysis in the gastrointestinal lumen and wall acting as mucoadhesive reservoirs. Eur J Pharmaceut Sci 2010; 39: 116-124.
18. Fiel LA, Contri RV, Bica JF, Figueiró F, Battastini AMO, Guterres SS. Labeling the oily core of nanocapsules and lipid-core nanocapsules with a triglyceride conjugated to a fluorescent dye as a strategy to particle tracking in biological studies. Nanoscale Res Lett 2014; 9: 233.
19. Li H, Zhao XB, Ma YK, Zhai GX, Li LB, Lou HX. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J Control Release 2009; 133: 238-244.
20. Clark CR, Dowling PM, Boison JO. Development and validation of a method for determination of tilmicosin residues in equine plasma and tissues using HPLC. J Liquid Chromatogr Related Tech 2009; 32: 2839-2856.
21. Qi J, Lu Y, Wu W. Absorption, disposition and pharmacokinetics of solid lipid nanoparticles. Curr Drug Metab 2012; 13: 418-428.
22. Smink W. Fatty acid digestion, synthesis and metabolism in broiler chickens and pigs. PhD, Wageningen University, Wageningen, the Netherlands, 2012.23. Harde H, Das M, Jain S. Solid lipid nanoparticles: an oral bioavailability enhancer vehicle. Expert Opin Drug Del 2011; 8: 1407-1424.
24. Manjunath K, Venkateswarlu V. Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration. J Control Release 2005; 107: 215-228.
25. Rege BD, Kao JP, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci 2002; 16: 237-246.
26. Jain D, Panda AK, Majumdar DK. Eudragit S 100 entrapped insulin microspheres for oral delivery. AAPS Pharm Sci Tech 2005; 6: 100-107.
27. Mohammadzadeh R, Baradaran B, Valizadeh H, Yousefi B, Zakeri-Milani P. Reduced ABCB1 expression and activity in the presence of acrylic copolymers. Adv Pharmaceut Bulletin 2014; 4: 219-224.
28. Aburahma MH, Badr-Eldin SM. Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nano-pharmaceuticals. Expert Opin Drug Del 2014; 11: 1865-1883.
29. Keleş O, Bakırel T, Şener S. Pharmacokinetics and tissue levels of tilmicosin in fowls. Turk J Vet Anim Sci 2001; 25: 629-634.
30. Fricke JA, Clark CR, Boison JO, Chirino-Trejo M, Inglis TES, Dowling PM. Pharmacokinetics and tissue depletion of tilmicosin in turkeys. J Vet Pharmacol Therap 2008; 31: 591-594.