Download PDF
Arzneimittelforschung 2010; 60(11): 682-688
DOI: 10.1055/s-0031-1296347
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

Effects of oral administration of synthesized δ-amides of eflornithine in the rat

Kevin J. Helena
1   Department of Pharmaceutical Chemistry, North-West University Potchefstroom, South Africa
,
David D. N’Da
1   Department of Pharmaceutical Chemistry, North-West University Potchefstroom, South Africa
,
Carl C. Johansson
2   Unit for Pharmacokinetics and Drug Metabolism, University of Gothenburg, Gothenburg, Sweden
,
Jaco C. Breytenbach
1   Department of Pharmaceutical Chemistry, North-West University Potchefstroom, South Africa
,
Michael Ashton
2   Unit for Pharmacokinetics and Drug Metabolism, University of Gothenburg, Gothenburg, Sweden
› Author Affiliations
Further Information

Publication History

Publication Date:
30 December 2011 (online)

    Permissions and Reprints

Abstract

The purpose of this study was to synthesize a series of δ-amide derivatives of the antitrypanosomal drug eflornithine (2,5-diamino-2-(difluoromethyl)pentanoic acid hydrochloride, DMFO, CAS 70052-12-9), to determine their physicochemical properties and to assess whether they convert to eflornithine in vivo and if so, whether higher systemic exposure to eflornithine could be achieved by increase intestinal absorption, suggesting an oral treatment to be possible. The derivatives were synthesized by amidation of eflornithine on its δ-amino group using acyl chlorides. The partition coefficients (log D, pH = 7.4) were found to be between −0.78 ± 1.07 and −0.07 ± 1.08 while the aqueous solubility (Sw), which as determined in phosphate buffered solution (pH 7.4), ranged from 11.13 ± 0.32 to 28.74 ± 0.36 mg/mL. The synthesized compounds were thus mostly more lipophilic than eflornithine itself (log D = −0.98 ± 0.88, Sw = 34.96 ± 0.37 mg/mL). The intestinal absorption was assessed by plasma analysis after oral administration of each compound to Sprague-Dawley rats. The biological data revealed that the derivatives were either not absorbed from the gastro-intestinal tract or not metabolized into eflornithine as no parent drug was detected in the plasma.

Key words

Amidation - Antitrypanosomal drug - CAS 70052-12-9 - Eflornithine, oral bioavailability - Human African trypanosomiasis (HAT)
 

  • References

  • 1 Simarro PP, Jannin J, Cattand P. Eliminating human African trypanosomiasis: Where do we stand and what comes next?. PloS Med. 2008; 5: e55
    CrossrefPubMedGoogle Scholar
  • 2 WHO. The global burden of disease: 2004 update. 2004. available at: http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_AnnexA.pdf Accessed Aug 18, 2009.
    PubMedGoogle Scholar
  • 3 Barrett MP. The fall and rise of sleeping sickness. Lancet. 1999; 353: 1113-4
    CrossrefPubMedGoogle Scholar
  • 4 Pépin J, Méda H. The epidemiology and control of human African trypanosomiasis. Adv Parasitol. 2001; 49: 71-132
    PubMedGoogle Scholar
  • 5 Wu G. Intestinal mucosal amino acid catabolism. J Nutr. 1998; 128: 1249-52
    PubMedGoogle Scholar
  • 6 Seed JR. African trypanosomiasis research: 100 years of progress, but questions and problems still remain. Int J Parasitol. 2000; 5–6: 434-42
    PubMedGoogle Scholar
  • 7 WHO. Control and surveillance of African trypanosomiasis: report of a WHO Expert Committee. Geneva: World Health Organization; 1998
    Google Scholar
  • 8 Schmidt GD, Roberts LS, Janovy J In: Foundations of parasitology. Brown WC, editor London: McGraw-Hill; 1999
    Google Scholar
  • 9 Balasegaram M, Young H, Chappuis F, Priotto G, Rague-naud M, Checchi F. Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes. Trans R Soc Trop Med Hyg. 2009; 103: 280-90
    CrossrefPubMedGoogle Scholar
  • 10 De Koning HP. Transporters in African trypanosomes: role in drug action and resistance. Int J Parasitol. 2001; 31: 512-22
    CrossrefPubMedGoogle Scholar
  • 11 Matovu E, Enyaru JCK, Legros D, Schmid C, Seebeck T, Ka-minsky R. Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda. Trop Med Int Health. 2001; 6: 407-11
    CrossrefPubMedGoogle Scholar
  • 12 Matovu E, Seebeck T, Enyaru JCK, Kaminsky R. Drug resistance in Trypanosoma brucei spp., the causative agents of sleeping sickness in man and nagana in cattle. Microb Infect. 2001; 3: 763-70
    CrossrefPubMedGoogle Scholar
  • 13 Bouteille B, Oukem O, Bisser S, Dumas M. Treatment perspectives for human African trypanosomiasis. Fundam Clin Pharmacol. 2003; 17: 171-81
    CrossrefPubMedGoogle Scholar
  • 14 Denise H, Barrett MP. Uptake and mode of action of drugs used against sleeping sickness. Biochem Pharmacol. 2001; 61: 1-5
    CrossrefPubMedGoogle Scholar
  • 15 McCann PP, Pegg AE. Ornithine decarboxylase as an enzyme target for therapy. Pharmacol Ther. 1992; 54: 195-215
    CrossrefPubMedGoogle Scholar
  • 16 Burri C, Brun R. Eflornithine for the treatment of human African trypanosomiasis. Parasitol Res. 2003; 90: S49-S52
    PubMedGoogle Scholar
  • 17 Phillips MA, Stanley Jr. SL In: The pharmacological basis of therapeutics: Chemotherapy of protozoal infections. Brunton LL, Lazo JS, Parker KL. editors. New York: McGraw-Hill; 2001. p. 1049-1072
    Google Scholar
  • 18 Chappuis F. Melarsoprol-free drug combinations for second-stage Gambian sleeping sickness: the way to go. Clin Infect Dis. 2007; 45: 1443-5
    CrossrefPubMedGoogle Scholar
  • 19 Balasegaram M, Harris S, Checchi F, Ghorashian S, Hamel C, Karunakara U. Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull WHO. 2006; 84: 783-91
    PubMedGoogle Scholar
  • 20 Zhang L, Wang X, Wang J, Grinberg N, Krishnamurthy D, Senanayake CH. An improved method of amide synthesis using acyl chlorides. Tetrahedron Let. 2009; 50: 2964-6
    CrossrefPubMedGoogle Scholar
  • 21 Jansson R, Malm M, Roth C, Ashton M. Enantioselective and nonlinear intestinal absorption of eflornithine in the rat. Antimicrob Agents Chemother. 2008; 52: 2842-8
    CrossrefPubMedGoogle Scholar
  • 22 Jansson-Löfmark R, Römsing S, Albers E, Ashton M. Determination of eflornithine enantiomers in plasma by pre-column derivatization with o-phthalaldehyde-N-acetyl-1-cysteine and liquid chromatography with UV detection. Biomed Chromatogr. 2010; 24: 794-7
    CrossrefPubMedGoogle Scholar
  • 23 Shargel L, Yu ABC. Physiologic factors related to drug absorption. In: Shargel L, Yu ABC. editors. Applied biophar-maceutics & pharmacokinetics. 4th ed. Stamford (CT): Appleton & Lange; 1999. p. 99-121
    Google Scholar
  • 24 McCann PP, Pegg AE. Ornithine decarboxylase as an enzyme target for therapy. Pharmacol Ther. 1992; 54: 195-215
    CrossrefPubMedGoogle Scholar
  • 25 Chollet C, Baliani A, Wong PE, Barrett MP, Gilbert IH. Targeted delivery of compounds to Trypanosoma brucei using the melamine motif. Bioorg Med Chem. 2009; 17: 2512-23
    CrossrefPubMedGoogle Scholar
  • 26 Caron G, Reymond F, Carrupt P, Girault HH, Testa B. Combined molecular lipophilicity descriptors and their role in understanding intramolecular effects. Pharm Sci Technol. 1999; 2: 327-335
    CrossrefPubMedGoogle Scholar
  • 27 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46: 3-26
    CrossrefPubMedGoogle Scholar
  • 28 Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999; 1: 55-68
    CrossrefPubMedGoogle Scholar
  • 29 Silverman RB. The organic chemistry of drug design and drug action. Amsterdam, Boston: Elsevier Academic Press; 2004
    Google Scholar