title: Synthesis, In Vitro and In Vivo Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a Prodrug.
abstract: The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester's half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1). The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. box 3030, Irbid 22110, Jordan. jamaljilani@yahoo.com.
authors.forename: Jamal A
authors.initials: JA
authors.lastname: Jilani
authors.affiliation: Faculty of Pharmacy, University of Petra, Amman 11196, Jordan. nidkaidek@uop.edu.jo.
authors.forename: Nasir M
authors.initials: NM
authors.lastname: Idkaidek
authors.affiliation: Department of Clinical Pharmacy, Jordan University of Science and Technology, P.O. box 3030, Irbid 22110, Jordan. khalzoubi@just.edu.jo.
authors.forename: Karem H
authors.initials: KH
authors.lastname: Alzoubi
references.citation: Int J Mol Sci. 2012 Nov 19;13(11):15305-20
references.pmid: 23203127
references.citation: Chem Biodivers. 2006 Nov;3(11):1238-48
references.pmid: 17193237
references.citation: J Med Chem. 2011 Mar 10;54(5):1202-10
references.pmid: 21250699
references.citation: Arch Pharm (Weinheim). 2007 Jan;340(1):32-40
references.pmid: 17206608
references.citation: J Pharm Sci. 1994 May;83(5):644-8
references.pmid: 8071813
references.citation: Curr Med Res Opin. 2012 Jan;28(1):163-78
references.pmid: 22168216
references.citation: Eur J Med Chem. 2005 Apr;40(4):371-6
references.pmid: 15804536
references.citation: J Med Chem. 2011 Mar 10;54(5):1191-201
references.pmid: 21284386
references.citation: Drug Metab Lett. 2012;6(4):235-41
references.pmid: 23879789
references.citation: J Control Release. 2001 Jan 29;70(1-2):183-91
references.pmid: 11166418
references.citation: Pharm Res. 1993 May;10(5):639-48
references.pmid: 8321828
references.citation: Biopharm Drug Dispos. 2002 Nov;23(8):307-15
references.pmid: 12415571
references.citation: J Med Chem. 2000 Oct 19;43(21):4005-16
references.pmid: 11052806
references.citation: Curr Med Res Opin. 2010 Jul;26(7):1715-31
references.pmid: 20470236
references.citation: Curr Drug Targets. 2001 Mar;2(1):79-106
references.pmid: 11465540
references.citation: JAMA. 2001 Aug 22-29;286(8):954-9
references.pmid: 11509060
references.citation: Eur J Med Chem. 2010 Jun;45(6):2591-6
references.pmid: 20227799
references.citation: Pharmazie. 2002 Aug;57(8):552-5
references.pmid: 12227196
references.citation: J Med Chem. 2000 Aug 10;43(16):3093-102
references.pmid: 10956217
references.citation: PDA J Pharm Sci Technol. 2010 Jul-Aug;64(4):348-55
references.pmid: 21502035