Pharmacokinetic study of furosemide incorporated PLGA microspheres after oral administration to rat

Document Type: Original Article


1 Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

3 Department of Pharmacology and Toxicology, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah


Objective(s): The purpose of the current study was to assess the feasibility of microspheres from biocompatible polymer for oral bioavailability (BA) enhancement of potent sulfonamide- type loop diuretic- Furosemide - which used in the treatment of congestive heart failure, caused edema, cirrhosis, renal disease and as an adjunct in acute pulmonary edema. The comparatively poor and inconstant BA of furosemide, which occurs site-specifically in the stomach and upper small intestine, has been ascribed to the poor dissolution of furosemide.
Materials and Methods: In attempt to enhance the drug BA, poly (dl-lactic-co-glycolic acid) (PLGA) microspheres of furosemide were obtained using solvent-evaporation method and the carrier characteristics were investigated subsequently.
Results: The in vivo performance of optimum formulation was assessed by pharmacokinetic evaluation of drug after orally administration of free and loaded in microspheres to rats (4 mg/Kg). For this reason, the concentration of drug in plasma was measured by a new developed and sensitive method of HPLC. Acceptable drug loading and encapsulation efficiency of microspheres were obtained to be 70.43 and 85.21 %, respectively. Microspheres provided improved pharmacokinetic parameters (Cmax = 147.94 ng/ml, Tmax = 1.92 hr) in rats as compared with pure drug (Cmax = 75.69 ng/ml, Tmax = 1.5 hr). The obtained AUC of drug in microsphere was 10 fold higher than of the free drug.
Conclusion: The results showed that the prepared microspheres successfully improved BA of the poorly water-soluble drug effectively.


1.Haznedar S, Dortunç B. Preparation and in vitro evaluation of Eudragit microspheres containing acetazolamide. Int J Pharm 2004; 269:131-140.

2.Wang Z, Chen B, Quan G,  Li F, Wu Q,  Dian L. Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica. Int J Nanomedicine 2012; 7: 5807–5818.

3.Huang JJ, Wigent RJ, Bentzley CM, Schwartz JB Nifedipine solid dispersion in microparticles of aminomethacrylate copolymer and ethylcellulose binary blend for controlled drug delivery: effect of drugloading on release kinetics. Int J Pharm 2006; 319: 44–45.

4.Wan Sh, Sun Y, Sun L, Tan F. Chitosan microparticles for oral bioavailability improvement of thehydrophobic drug curcumin. Pharmazie 2012; 67: 525–528.

5.Song Z, Feng R, Sun M, Guo C, Gao Y, Li L, Zhai G. Curcumin-loaded PLGA-PEG-PLGA triblockcopolymeric micelles: Preparation, pharmacokinetics and distribution in vivo. J Colloid Interface Sci 2011; 354: 116–123.

6.Dawes GJS, Fratila-Apachitei LE, Mulia K, Apachitei I, Witkamp G-J, Duszczyk J Size effect of PLGA spheres on drug loading efficiency and release profiles. J Mater Sci Mater Med 2009; 20: 1089–1094.

7.Afshari M, Derakhshandeh K, Hosseinzadeh L. Characterisation, cytotoxicity and apoptosis studies of methotrexate-loaded PLGA and PLGA-PEG nanoparticles. J Microencapsul 2014; 31: 239-245.

8.Derakhshandeh, K., Fathi, S. Role of chitosan nanoparticles in the oral absorption of Gemcitabine. Int J Pharm 2012; 437: 172-177.

9.Gentile P, Chiono V, Carmagnola I,  Hatton PV. An Overview of Poly (lactic-co-glycolic) Acid (PLGA)-Based Biomaterials for Bone Tissue Engineering. Int J Mol Sci 2014; 15: 3640–3659.

10.Ramesh V, Sairam M, Kallappa M, Aminabhavi M. Preparation of sodium alginate–methylcellulose blend microspheres for controlled release of nifedipine. Carbohydrate Polymers. 2007; 69: 241-250.

11.Cooper DL, Wood RC, Wyatt JE, Harirforoosh S. Pharmacokinetic interactions between rebamipide and selected nonsteroidal anti-inflammatory drugs in rats. Eur J Pharm Sci 2014; 53: 28-34.

12.Ezan E. Pharmacokinetic studies of protein drugs: Past, present and future. Adv Drug Deliv Rev. 2013; 65:1065–1073.

13.Kirchhofer C, Vargas M, Huwyler J, Keiser J. Pharmacokinetics of the fasciocidal drug candidates MT04 and OZ78 in uninfected rats and in vitro pharmacodynamics studies.Int J Parasitol Drugs Drug Resist. 2012; 2: 121–125.

14.Sun F, Sui C, Teng L, Liu X, Teng L, Meng Q, Li Y. Studies on the preparation, characterization and pharmacological evaluation of tolterodine PLGA microspheres. Int J Pharm 2010; 397: 44–49.

15.Nagahara N, Akiyama Y, Higaki K, Kimura T. Animal models for predicting potency of oral sustained-release adhesive microspheres in humans. Int J Pharm 2007; 331: 46–53.

16.He Z, Wan X, Schulz A, Bludau H, Dobrovolskaia MA, Stern ST, Montgomery SA, Yuan H, Li Z, Alakhova D, Sokolsky M, Darr DB, A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials 2016; 101: 296–309.

17.Lindenberg M, Kopp S, Dressman B. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 2004; 58:265-278.

18.Derakhshandeh K, Hosseinalizadeh A, Nikmohammadi M. The effects of PLGA microparticles on intestinal absorption of P-glycoprotein substrate using the everted rat intestinal sac model. Arch Pharm Res 2011; 34:1989-1997.

19.Derakhshandeh, K., Erfan, M., Dadashzadeh, S. Encapsulation of 9-nitrocamptothecin, a novel   anticancer drug, in biodegradable nanoparticles: factorial design, characterization and release kinetics. Eur J Pharm Biopharm. 2007; 66:34-41.

20.Derakhshandeh K, Soheili M, Dadashzadeh S, Saghiri R. Preparation and in vitro characterization of 9-nitrocamptothecin-loaded long circulating nanoparticles for delivery in cancer patients. Int J Nanomed 2010; 5:463–471.

21.Derakhshandeh K, Hochhaus G, Dadashzadeh, S. In vitro cellular uptake and transport study of 9-nitrocamptothecin PLGA nanoparticles across Caco-2 cell monolayer model. Iran J Pharm Res 2011; 10: 425-434.

22.Shargel L. Applied Biopharmaceutics & Pharmacokinetics. 5th ed. USA: Appleton and longe; 2004.p. 146-175.

23.López-Arnau R, Martínez-Clemente J, Carbó M, Pubill D, Escubedo E, Camarasa J. An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as “bath salts”. Prog Neuro-psychopharmacol & Biol Psychiatry 2013; 45:64–72.

24.Lin ET, Smith DE, Benet L, Hoener BA. High-perfo rmance Iiquid chromatographic assays for furosemide in plasma and urine. J Chromatography 1979; 163:315-321.

25.Carolina gomez G, Carlos von Plessing R, C. Gloria Godoy M, Rolando Reinbach H, Ricardo Godoy R. Method validation for the determination of furosemide in plasma by liquid- liquid extraction and high-performance liquid chromatography with fluorescence detection. J Chil Chem Soc 2005; 50: 479-482.  

26.Chen J, Ping Q, Guo J, Chu X, Song M. Pharmacokinetics of lactone, carboxylate and total 9-nitrocamtothecin with different doses and administration routes in rats. Biopharm Drug Dispos 2006; 27:53–59.

27.Ratajczak-Enselme M, Estebe JP, Dollo G, Chevanne F, Bec D, Malinovsky JM. Epidural, intrathecal and plasma pharmacokinetic study of epidural ropivacaine in PLGA-microspheres in sheep model. Eur J Pharm Biopharm 2009; 72:54-61.

28.Dadashzadeh S, Derakhshandeh K, HoseiniShirazi F. 9-Nitrocamptothecin polymeric nanoparticles: cytotoxicity and pharmacokinetic studies of lactone and total forms of drug in rats. Anti-Cancer Drugs 2008; 19:805–811.

29.Onishi H, Machida Y, Machida Y. Antitumor properties of irinotecan containing nanoparticles prepared using poly (DL-lactic acid) and poly (ethylene glycol)-block-poly (propylene glycol) - block poly (ethylene glycol). Biol Pharm Bull 2003; 26:116–119.

30.Reddy HL, Murthy RSR. Pharmacokinetics and biodistribution studies of doxorubicin loaded poly (butyl cyanoacrylate) nanoparticles synthesized by two different techniques. Biomed Pap 2004; 148:161–166.

31.Narayanan S, Pavithran M, Viswanath A,  Narayanan D,  Mohan CC, Manzoor K. Sequentially releasing dual- drug-loaded PLGA–casein core/shell nanomedicine: Design, synthesis, biocompatibility and pharmacokinetics. Acta Biomaterialia 2014; 10:2112–2124.

32.Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer-mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Cancer Sci 2000; 11:265–283.

33.Derakhshandeh K, Nikmohammadi M, HosseinalizadehA. The effects of PLGA microparticles on intestinal absorption of P-glycoprotein substrate by the everted rat intestinal sac model. Arch Pharm Res 2011; 34:1989-1997.

34.Rassu G, Soddu E, Cossu M, Brundu A, Cerri G, 

Marchetti N, Ferraro L, Regan RF, Giunchedi P, Gavini E, Dalpiaz A. Solid microparticles based on chitosan or methyl-β-cyclodextrin: A first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. J Control Release 2015; 201: 68–77.

35.Marais E, amman J, du Plessis L, Lemmer  R, Steenekamp J. Eudragit L100/N-Trimethyl chitosan Chloride microspheres for oral insulin delivery. Molecules 2013; 18:6734-6747.

36.Fasano A. Novel approaches for oral delivery of macromolecules. J Pharm Sci 1998; 87:1351-1356.

37.Booysen LL, Kalombo L, Brooks E, Hansen R, Gilliland J, Gruppo V. In vivo/in vitro pharmacokinetic and pharmacodynamic study of spray-dried poly-(dl-lactic-co-glycolic) acid nanoparticles encapsulating rifampicin and isoniazid. Int J Pharm 2013; 444:10–17.