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

Anelize Bauermeister; Fernando Armani Aguiar; Lucas Maciel Mauriz Marques; Jose Dos Santos Malta Jr.; Fábio Barros; Daniel Roberto Callejon; Anderson Rodrigo Moraes de Oliveira; Norberto Peporine Lopes

doi:10.1055/s-0042-111732

Planta Medica, Inhaltsverzeichnis

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

¹Núcleo 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

¹Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil

⁵Departamento de Química, Universidade Federal do Rio de Janeiro – Campus Macaé, Macaé, Rio de Janeiro, Brazil

,

Lucas Maciel Mauriz Marques

¹Núcleo 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.

²Vita Nova, Hortolândia, São Paulo, Brazil

,

Fábio Barros

²Vita Nova, Hortolândia, São Paulo, Brazil

,

Daniel Roberto Callejon

¹Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil

⁴Lychnoflora Pesquisa e Desenvolvimento em Produtos Naturais LTDA, Ribeirão Preto, São Paulo, Brazil

,

Anderson Rodrigo Moraes de Oliveira

³Laboratório 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

¹Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil

› Institutsangaben

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

Volltext

Referenzen

References
1 Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 2003; 43: 144-166
2 Tepper SJ. Orally inhaled dihydroergotamine: a review. Headache 2013; 53: 43-53
3 Mondell B, Diserio F, Friedman A. Dihydroergotamine nasal spray in the acute treatment of migraine headache. Clin Pharmacol Ther 1989; 45: 161
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
5 Silberstein SD. The pharmacology of ergotamine and dihydroergotamine. Headache 1997; 37 (Suppl. 01) S15-S25
6 Muller-Schweinitzer E. Pharmacological actions of the main metabolites of dihydroergotamine. Eur J Clin Pharmacol 1984; 26: 699-705
7 Montellano PRO. Cytocrome P-450: Structure, Mechanism e Biochemistry. 2nd. edition. New York: Plenum Publishers; 2005
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
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
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
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
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
13 Lohmann W, Karst U. Biomimetic modeling of oxidative drug metabolism. Anal Bioanal Chem 2008; 391: 79-96
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
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
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
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
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
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
20 Sharefkin JG, Saltzman H. Organic Syntheses Collective. Organic Syntheses, Inc.; 1973. Volume 5. 660
21 Lucas HJ, Kenedy ER, Forno MW. Organic Syntheses Collective. Organic Syntheses, Inc.; 1963. Volume 43. 62

Zusatzmaterial

Supporting Information