Download PDF
Planta Med 2016; 82(15): 1368-1373
DOI: 10.1055/s-0042-111732
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

In Vitro Metabolism Evaluation of the Ergot Alkaloid Dihydroergotamine: Application of Microsomal and Biomimetic Oxidative Model

Anelize Bauermeister
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
,
Fernando Armani Aguiar
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
5   Departamento de Química, Universidade Federal do Rio de Janeiro – Campus Macaé, Macaé, Rio de Janeiro, Brazil
,
Lucas Maciel Mauriz Marques
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
,
Jose Dos Santos Malta Jr.
2   Vita Nova, Hortolândia, São Paulo, Brazil
,
Fábio Barros
2   Vita Nova, Hortolândia, São Paulo, Brazil
,
Daniel Roberto Callejon
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
4   Lychnoflora Pesquisa e Desenvolvimento em Produtos Naturais LTDA, Ribeirão Preto, São Paulo, Brazil
,
Anderson Rodrigo Moraes de Oliveira
3   Laboratório de Metabolismo In Vitro e Técnicas de Separação, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
,
Norberto Peporine Lopes
1   Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
› Author Affiliations
Further Information

Publication History

received 12 May 2016
revised 27 June 2016

accepted 28 June 2016

Publication Date:
02 August 2016 (online)

Also available at
    Permissions and Reprints

Abstract

Dihydroergotamine is a semisynthetic natural product derived from ergotamine, an ergot alkaloid. It is used to treat migraines, a neurological disease characterized by recurrent moderate to severe headaches. In this work, the in vitro metabolism of dihydroergotamine was evaluated in a biomimetic phase I reaction, aiming to verify all possible formed metabolites. Dihydroergotamine was submitted to an in vitro metabolism assay using rat liver microsomes, and the metabolites were analyzed by HPLC-MS/MS. The biomimetic reactions were performed with Jacobsen catalyst for scaling up production of oxidized metabolites. Two hydroxylated metabolites were isolated and characterized by MS/MS and 1H NMR analysis.

Key words

Claviceps purpurea - Clavicipitaceae - Dihydroergotamine - in vitro metabolism - Jacobsen catalyst - microsomal model

Supporting Information

 

  • References

  • 1 Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 2003; 43: 144-166
    CrossrefPubMedGoogle Scholar
  • 2 Tepper SJ. Orally inhaled dihydroergotamine: a review. Headache 2013; 53: 43-53
    CrossrefPubMedGoogle Scholar
  • 3 Mondell B, Diserio F, Friedman A. Dihydroergotamine nasal spray in the acute treatment of migraine headache. Clin Pharmacol Ther 1989; 45: 161
    PubMedGoogle Scholar
  • 4 Chen XY, Zhong DF, Xu HY, Schug B, Blume H. Sensitive and specific liquid chromatographic-tandem mass spectrometric assay for dihydroergotamine and its major metabolite in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 768: 267-275
    CrossrefPubMedGoogle Scholar
  • 5 Silberstein SD. The pharmacology of ergotamine and dihydroergotamine. Headache 1997; 37 (Suppl. 01) S15-S25
    CrossrefPubMedGoogle Scholar
  • 6 Muller-Schweinitzer E. Pharmacological actions of the main metabolites of dihydroergotamine. Eur J Clin Pharmacol 1984; 26: 699-705
    CrossrefPubMedGoogle Scholar
  • 7 Montellano PRO. Cytocrome P-450: Structure, Mechanism e Biochemistry. 2nd. edition. New York: Plenum Publishers; 2005
    Google Scholar
  • 8 Chorghade MS, Hill DR, Lee EC, Pariza RJ. Metalloporphyrins as chemical mimics of cytochrome P-450 systems. Pure Appl Chem 1996; 68: 753-756
    PubMedGoogle Scholar
  • 9 Pigatto MC, de Lima MDA, Galdino SL, Pitta ID, Vessecchi R, Assis MD, dos Santos JS, Costa TD, Lopes NP. Metabolism evaluation of the anticancer candidate AC04 by biomimetic oxidative model and rat liver microsomes. Eur J Med Chem 2011; 46: 4245-4251
    CrossrefPubMedGoogle Scholar
  • 10 Guaratini T, Silva DB, Bizaro AC, Sartori LR, Humpf HU, Lopes NP, Costa-Lotufo LV, Lopes JLC. In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna . BMC Complement Altern Med 2014; 14: 61
    CrossrefPubMedGoogle Scholar
  • 11 Verza M, Arakawa NS, Lopes NP, Kato MJ, Pupo MT, Said S, Carvalho I. Biotransformation of a tetrahydrofuran lignan by the endophytic fungus Phomopsis sp. J Braz Chem Soc 2009; 20: 195-200
    CrossrefPubMedGoogle Scholar
  • 12 Melo AJB, Iamamoto Y, Maestrin APJ, Smith JRL, Santos MD, Lopes NP, Bonato PS. Biomimetic oxidation of praziquantel catalysed by metalloporphynins. J Mol Catal A Chem 2005; 226: 23-31
    CrossrefPubMedGoogle Scholar
  • 13 Lohmann W, Karst U. Biomimetic modeling of oxidative drug metabolism. Anal Bioanal Chem 2008; 391: 79-96
    CrossrefPubMedGoogle Scholar
  • 14 Niehues M, Barros VP, Emery FD, Dias-Baruffi M, Assis MD, Lopes NP. Biomimetic in vitro oxidation of lapachol: a model to predict and analyse the in vivo phase I metabolism of bioactive compounds. Eur J Med Chem 2012; 54: 804-812
    CrossrefPubMedGoogle Scholar
  • 15 Mac Leod TCO, Barros VP, Faria AL, Schiavon MA, Yoshida IVP, Queiroz MEC, Assis MD. Jacobsen catalyst as a P450 biomimetic model for the oxidation of an antiepileptic drug. J Mol Catal A Chem 2007; 273: 259-264
    CrossrefPubMedGoogle Scholar
  • 16 Mac Leod TCO, Faria AL, Barros VP, Queiroz MEC, Assis MD. Primidone oxidation catalyzed by metalloporphyrins and Jacobsen catalyst. J Mol Catal A Chem 2008; 296: 54-60
    CrossrefPubMedGoogle Scholar
  • 17 Higuchi T, Hirobe M. Four recent studies in cytochrome P450 modelings: A stable iron porphyrin coordinated by a thiolate ligand; a robust ruthenium porphyrin-pyridine N-oxide derivatives system; polypeptide-bound iron porphyrin; application to drug metabolism studies. J Mol Catal A Chem 1996; 113: 403-422
    CrossrefPubMedGoogle Scholar
  • 18 Ferreira LD, Callejon DR, Engemann A, Cramer B, Humpf HU, de Barros VP, Assis MD, da Silva DB, de Albuquerque S, Okano LT, Kato MJ, Lopes NP. In vitro metabolism of grandisin, a lignan with anti-chagasic activity. Planta Med 2012; 78: 1939-1941
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Demarque DP, Crotti AEM, Vessecchi R, Lopes JLC, Lopes NP. Fragmentation reactions using electrospray ionization mass spectrometry: An important tool for the structural elucidation and characterization of synthetic and natural products. Nat Prod Rep 2016; 33: 432-455
    CrossrefPubMedGoogle Scholar
  • 20 Sharefkin JG, Saltzman H. Organic Syntheses Collective. Organic Syntheses, Inc.; 1973. Volume 5. 660
    Google Scholar
  • 21 Lucas HJ, Kenedy ER, Forno MW. Organic Syntheses Collective. Organic Syntheses, Inc.; 1963. Volume 43. 62
    Google Scholar