Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

Pharmacokinetic Profile of Oxaliplatin-Loaded pH-Responsive Hydrogels in Rabbits

Author(s): Kaleem Ullah, Shujaat Ali Khan*, Muhammad Sohail, Abdul Mannan and Ghulam Murtaza

Volume 26 , Issue 44 , 2020

Page: [5755 - 5763] Pages: 9

DOI: 10.2174/1381612826666200813125159

Price: $65

Abstract

Background: Oxaliplatin (OXP), a 3rd generation platinum compound, which causes severe side effects due to; impulse high concentration in the bloodstream thereby exposing healthy cells at a high ratio, nonspecific delivery at the target site and non-compliance is administered intravenously.

Objective: The project was aimed at the development, characterization, and in-vitro and in-vivo evaluation of pHresponsive hydrogels for oral administration of OXP.

Methods: Hydrogel formulations were synthesized through a free radical polymerization technique followed by brief characterization using various techniques. The hydrogels were investigated for various in-vitro studies such as sol-gel, drug loading, swelling, drug release, and MTT-assay. While in-vivo studies such as oral tolerability, histopathology, and hematology studies were performed on rabbits. A simple and sensitive HPLC-UV method was optimized and the comparative pharmacokinetic study was performed in rabbits using OXP-oral solution and OXP-loaded hydrogels.

Results: In-vitro characterization confirmed that the reactant was successfully crosslinked to form thermally stable hydrogels with decreased crystallinity and rough surface. Swelling and drug release showed that hydrogels were more responsive to basic pH (6.8 and 7.4) in comparison with pH 1.2. The blank hydrogels were cytocompatible as more than 95% of the cells were viable while free OXP and OXP-loaded hydrogels displayed dosedependent cytotoxic effect. In-vivo studies confirmed that chitosan and gelatin hydrogel suspension was well tolerable up to 3800 mg/kg and 4000 mg/kg of body weight, respectively. Hematology and serum chemistry reports were well within the range suggesting normal liver and kidney functions. Similarly, histopathology slides of rabbit vital organs were also found normal without causing any histopathological change.

Conclusion: HPLC-UV method was successfully optimized for OXP detection in oral solution and hydrogels administered to rabbits. A significant difference was found among various pharmacokinetic parameters by comparing the two groups including half-life (t1/2), tmax, Cmax, AUCtot MRT, Vz, and Lz.

Keywords: Oxaliplatin, colorectal cancer, hydrogels, chromatography, pharmacokinetics, polymerization.

[1]
Bénard F, Barkun AN, Martel M, von Renteln D. Systematic review of colorectal cancer screening guidelines for average-risk adults: Summarizing the current global recommendations. World J Gastroenterol 2018; 24(1): 124-38.
[http://dx.doi.org/10.3748/wjg.v24.i1.124] [PMID: 29358889]
[2]
Ito H, Yamaguchi H, Fujikawa A, et al. A full validated hydrophilic interaction liquid chromatography-tandem mass spectrometric method for the quantification of oxaliplatin in human plasma ultrafiltrates. J Pharm Biomed Anal 2012; 71: 99-103.
[http://dx.doi.org/10.1016/j.jpba.2012.08.010] [PMID: 22954448]
[3]
Chibaudel B, Tournigand C, André T, de Gramont A. Therapeutic strategy in unresectable metastatic colorectal cancer. Ther Adv Med Oncol 2012; 4(2): 75-89.
[http://dx.doi.org/10.1177/1758834011431592] [PMID: 22423266]
[4]
Matos BN, Pereira MN. Chitosan nanoparticles loading oxaliplatin as a mucoadhesive topical treatment of oral tumors: Iontophoresis further enhances drug delivery ex vivo. Int J Biol Macromol 2019; 154: 1265-75.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.11.001] [PMID: 31726173]
[5]
Jia X, Han Y, Pei M, et al. Multi-functionalized hyaluronic acid nanogels crosslinked with carbon dots as dual receptor-mediated targeting tumor theranostics. Carbohydr Polym 2016; 152: 391-7.
[http://dx.doi.org/10.1016/j.carbpol.2016.06.109] [PMID: 27516286]
[6]
Li B, Meng Z, Li Q, et al. A pH responsive complexation-based drug delivery system for oxaliplatin. Chem Sci (Camb) 2017; 8(6): 4458-64.
[http://dx.doi.org/10.1039/C7SC01438D] [PMID: 28970876]
[7]
Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22(47): 7265-79.
[http://dx.doi.org/10.1038/sj.onc.1206933] [PMID: 14576837]
[8]
Welch S, Spithoff K, Rumble RB, Maroun J, Group GCDS. Gastrointestinal Cancer Disease Site Group. Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol 2010; 21(6): 1152-62.
[http://dx.doi.org/10.1093/annonc/mdp533] [PMID: 19942597]
[9]
Hanada K, Suda M, Kanai N, Ogata H. Pharmacokinetics and toxicodynamics of oxaliplatin in rats: application of a toxicity factor to explain differences in the nephrotoxicity and myelosuppression induced by oxaliplatin and the other platinum antitumor derivatives. Pharm Res 2010; 27(9): 1893-9.
[http://dx.doi.org/10.1007/s11095-010-0189-4] [PMID: 20552253]
[10]
Kloft C, Appelius H, Siegert W, Schunack W, Jaehde U. Determination of platinum complexes in clinical samples by a rapid flameless atomic absorption spectrometry assay. Ther Drug Monit 1999; 21(6): 631-7.
[http://dx.doi.org/10.1097/00007691-199912000-00009] [PMID: 10604824]
[11]
Morrison JG, White P, McDougall S, et al. Validation of a highly sensitive ICP-MS method for the determination of platinum in biofluids: application to clinical pharmacokinetic studies with oxaliplatin. J Pharm Biomed Anal 2000; 24(1): 1-10.
[http://dx.doi.org/10.1016/S0731-7085(00)00377-0] [PMID: 11108533]
[12]
Ficarra R, Ficarra P, Tommasini S, et al. Validation of a LC method for the analysis of zafirlukast in a pharmaceutical formulation. J Pharm Biomed Anal 2000; 23(1): 169-74.
[http://dx.doi.org/10.1016/S0731-7085(00)00266-1] [PMID: 10898167]
[13]
Ficarra R, Calabrò ML, Cutroneo P, et al. Validation of a LC method for the analysis of oxaliplatin in a pharmaceutical formulation using an experimental design. J Pharm Biomed Anal 2002; 29(6): 1097-103.
[http://dx.doi.org/10.1016/S0731-7085(02)00151-6] [PMID: 12110395]
[14]
Matos BN. Development and validation of a simple and selective analytical HPLC method for the quantification of oxaliplatin. J Chem 2015; 2015812701
[15]
Anwar H, Ahmad M, Minhas MU, Rehmani S. Alginate-polyvinyl alcohol based interpenetrating polymer network for prolonged drug therapy, Optimization and in-vitro characterization. Carbohydr Polym 2017; 166: 183-94.
[http://dx.doi.org/10.1016/j.carbpol.2017.02.080] [PMID: 28385222]
[16]
Ullah K, Sohail M, Buabeid MA, et al. Pectin-based (LA-co-MAA) semi-IPNS as a potential biomaterial for colonic delivery of oxaliplatin. Int J Pharm 2019; 569118557
[http://dx.doi.org/10.1016/j.ijpharm.2019.118557] [PMID: 31377405]
[17]
Ullah K, Ali Khan S, Murtaza G, et al. Gelatin-based hydrogels as potential biomaterials for colonic delivery of oxaliplatin. Int J Pharm 2019; 556: 236-45.
[http://dx.doi.org/10.1016/j.ijpharm.2018.12.020] [PMID: 30553956]
[18]
Ullah K, Sohail M, Mannan A, et al. Facile synthesis of chitosan based-(AMPS-co-AA) semi-IPNs as a potential drug carrier: enzymatic degradation, cytotoxicity, and preliminary safety evaluation. Curr Drug Deliv 2019; 16(3): 242-53.
[http://dx.doi.org/10.2174/1567201815666181024152101] [PMID: 30360742]
[19]
Jankaew R, Rodkate N, Lamlertthon S, et al. “Smart” carboxymethylchitosan hydrogels crosslinked with poly (N-isopropylacrylamide) and poly (acrylic acid) for controlled drug release. Polym Test 2015; 42: 26-36.
[http://dx.doi.org/10.1016/j.polymertesting.2014.12.010]
[20]
Administration D Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers Center for Drug Evaluation and Research. CDER 2005.
[21]
Burz C, Berindan-Neagoe IB, Balacescu O, et al. Clinical and pharmacokinetics study of oxaliplatin in colon cancer patients. J Gastrointestin Liver Dis 2009; 18(1): 39-43. PMID: 19337632
[22]
Ehrsson H, Wallin I, Yachnin J. Pharmacokinetics of oxaliplatin in humans. Med Oncol 2002; 19(4): 261-5.
[http://dx.doi.org/10.1385/MO:19:4:261] [PMID: 12512920]
[23]
Liu J, Kraut E, Bender J, et al. Pharmacokinetics of oxaliplatin (NSC 266046) alone and in combination with paclitaxel in cancer patients. Cancer Chemother Pharmacol 2002; 49(5): 367-74.
[http://dx.doi.org/10.1007/s00280-002-0426-6] [PMID: 11976830]
[24]
Urbanska AM, Karagiannis ED, Guajardo G, Langer RS, Anderson DG. Therapeutic effect of orally administered microencapsulated oxaliplatin for colorectal cancer. Biomaterials 2012; 33(18): 4752-61.
[http://dx.doi.org/10.1016/j.biomaterials.2012.03.023] [PMID: 22472433 ]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy