Publicado

2016-09-01

Antecedentes del estudio metabólico de MDPV y metilona. Propuesta de un modelo de biotransformación a través de hongos del género Cunninghamella

History of the metabolic study of MDPV and methylone. Proposal of a biotransformation model through fungi of the genus Cunninghamella

DOI:

https://doi.org/10.15446/rcciquifa.v45n3.62055

Palabras clave:

MDPV, metilona, biotransformación, Cunninghamella (es)
MDPV, methylone, biotransformations, Cunninghamella (en)

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Autores/as

  • Eliana A. Silva Universidad Nacional de Colombia, Departamento de Farmacia
  • Jorge A. Martínez Laboratorio de Estupefacientes Instituto Nacional de Medicina Legal y Ciencias Forenses, Regional Bogotá, Colombia

La (±)-3,4-metilendioxipirovalerona (MDPV) y la (±)-3,4-metilenedioximetilcatinona (metilona) son algunos de los derivados sintéticos de catinonas más frecuentemente encontrados en productos que se comercializan como “sales de baño” y que hoy en día se emplean como drogas de abuso. Los reportes de casos fatales por consumo de estas sustancias aumentan cada día, y aunque existen algunos estudios farmacológicos y toxicológicos, no son claros los mecanismos de acción y los efectos causados por su consumo recreativo. La implementación de sistemas que permitan conocer el metabolismo de estas drogas en humanos y el diseño de métodos analíticos para su detección son ahora objeto de investigación.

 

Este artículo presenta una revisión bibliográfica acerca de los estudios de biotransformación para MDPV y metilona empleando modelos in vitro con microsomas hepáticos humanos, fracciones celulares S9 y modelos in vivo con animales de experimentación y posterior análisis de los metabolitos que hay hasta la fecha. Las técnicas analíticas utilizadas para el análisis de metabolitos incluyen cromatografía líquida acoplada a detector selectivo de masas (LC-MS o LC-MS/MS) o la formación de derivados acetilados o sililados para su posterior análisis por cromatografía de gases acoplada a detector selectivo de masas (GC-MS). Además, se incluye una propuesta para el estudio del metabolismo para metilona y MDPV a través de hongos del género Cunninghamella.

(±)-3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylendioxymethylcathi-none (methylone) are some of the most frequent synthetic derivatives of cathinones found in commercial products known as "Bath salts" and which today are used as drugs of abuse. Reports on fatal cases involving the consumption of these substances are raising and although there are some pharmacological and toxicological studies, their action mechanisms and effects due recreational consumption are not very well understood. The implementation of systems that allows the understanding of the metabolism of these drugs in humans and the design of analytical methods for their detection is now the subject of research. This paper shows a bibliographical review of the studies conducted on the biotransformation of methylone and MDPV using in vitro models with human hepatic microsomes, cell fractions S9 and in vivo models in animals with posterior analysis of the obtained metabolites. The analytical techniques used for the analysis of the metabolites include liquid chromatography coupled with mass spectrometry (LC-MS or LC-MS/MS) or the formation of acetylated or dimethyl silylated derivatives for their posterior analysis by gas chromatography (GC-MS). A proposal for the study of the metabolisms of methylone and MDPV through the fungus of the genera Cunninghamella is also included.

Referencias

(1) UNODC, Oficina de las Naciones Unidas Contra la Droga y el delito "Informe Mundial sobre las Drogas 2015. Resumen Ejecutivo", UNODC Research, 2015.

(2) UNODC, Afiche: Categorías de nuevas sustancias psicoactivas vendidas en el mercado. Laboratory and Forensic Science, 2014.

(3) K.A. Seely, J. Lapoint, J. H. Moran, L. Fattore, Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids, Prog. Neuropsychopharmacol. Biol. Psych., 39, 234-243 (2012).

(4) J.M. Prosser, L.S. Nelson, The toxicology of bath salts: A review of synthetic cathinones, J. Med. Toxicol., 8, 33-42 (2012).

(5) K. Miotto, J. Striebel, A.K. Cho, C. Wang, Clinical and pharmacological aspects of bath salt use: A review of the literatura and case reports, Drug Alcohol Depend., 132, 1-12 (2013).

(6) K. Liveri, M.A. Constantinou, M. Afxentiou, P. Kanari, A fatal intoxication related to MDPV and pentedrone combined with antipsychotic and antidepressant substances in Cyprus, Forensic Sci. Int., 265, 160-165 (2016).

(7) UNODC, Early Warning Advisory on New Psychoactive Substances NPS Substance Groups, URL: https://www.unodc.org/LSS/Substance?testType=NPS , consultado el 2 de febrero de 2016.

(8) S. Gibbons, M. Zloh, An analysis of the 'legal high' mephedrone, Bioorganic Med. Chem. Lett., 20, 4135-4139 (2010).

(9) S. Strano-Rossi, A.B. Cadwallader, X. de la Torre, F. Botrè, Toxicological determination and in vitro metabolism of the designer drug methylenedioxypyrovalerone (MDPV) by gas chromatography/mass spectrometry and liquid chromatography/quadrupole time-of-flight mass spectrometry, Rapid Commun. Mass Spectr., 24(18), 2706-2714 (2010).

(10) M.R. Meyer, P. Du, F. Schuster, H.H. Maurer, Studies on the metabolism of the a-pyrrolidinophenone designer drug methylenedioxypyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS, J. Mass Spectrom., 45(12), 1426-1442 (2010).

(11) S. Anizan, K. Ellefsen, M. Concheiro, M. Suzuki, K.C. Rice, M.H. Baumann, M.A. Huestis, 3,4-Methylenedioxypyrovalerone (MDPV) and metabolites quantification in human and rat plasma by liquid chromatography-high resolution mass spectrometry, Anal. Chim. Acta, 827, 54-63 (2014).

(12) F.T. Peters, M.R. Meyer, In vitro approaches to studying the metabolism of new psychoactive compounds, Drug Test. Anal., 3(7-8), 483-495 (2011).

(13) S.F. Imam, H. Patel, M. Mahmoud, N. A. Prakash, M.S. King, Bath salts intoxication: A case series, J. Emerg. Med., 45(3), 361-365 (2013).

(14) H.T. Kamata, N. Shima, K. Zaitsu, T. Kamata, M. Nishikawa, M. Katagi et al., Simultaneous analysis of new designer drug, methylone, and its metabolites in urine by gas chromatography-mass spectrometry and liquid chromatography-electrospray ionization mass spectrometry, Japan J. Forensic Sci. Tech., 12(1), 97-106 (2007).

(15) Expert Commite on Drug Dependence, Methylone (bk-MDMA), Critical Review Report, Word Health Organization, Geneva, 16-20 June, 2014.

(16) A. Dines, D. Wood, P. Dargan, Technical Report on 1-(1,3-benzodioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-one (3,4-methylenedioxypyrovalerone, MDPV), Lisbon: European Monitoring Centre for Drug and Addiction EMCDDA, 2014.

(17) Boehringer Ingelheim, α-Substituted-ketones and processes for their preparation, British patent, 1969, 23.1:149, 366.

(18) M. Coppola, R. Mondola, 3,4-Methylenedioxypyrovalerone (MDPV): Chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online, Toxicol. Lett., 208, 12-15 (2012).

(19) M. Mardal, M. Meyer, Studies on the microbial biotransformation of the novel psychoactive substance methylenedioxypyrovalerone (MDPV) in wastewater by means of liquid chromatography-high resolution mass spectrometry/mass spectrometry, Sci. Total Environ, 493, 588-595 (2014).

(20) S. Asha, M. Vidyavathi, Cunninghamella - A microbial model for drug metabolism studies - A review, Biotechnol. Adv., 27, 16-29 (2009).

(21) L. Sun, H. Huang, L. Liu, D. Zhong, Transformation of verapamil by Cunninghamella blakesleeana, Appl. Environ. Microbiol., 70(5), 2722-2727 (2004).

(22) B. Ma, H. Huang, X. Chen, Y. Sun, L. Lin, D. Zhong, Biotransformation of metoprolol by the fungus Cunninghamella blakesleeana, Acta Pharmacol. Sin., 28(7), 1067-1074 (2007).

(23) D. Zhong, L. Sun, L Liu, H. Huang, Microbial transformation of naproxen by Cunninghamella species, Acta Pharmacol. Sin., 24(5), 442-447 (2003).

(24) J. Moody, D. Zhang., T.M. Heinze, C.E. Cerniglia, Transformation of amoxapine by Cunninghamella elegans, Appl. Environ. Microbiol., 66(8), 3646-3649 (2000).

(25) Y. Toyokazu, M. Kitol, M. Tsujii, N. Toru, Microbial synthesis of a proton pump inhibitor by enantioselective oxidation of a sulfide into its corresponding sulfoxide by Cunninghamella echinulata MK40, Biotechnol. Lett., 23, 1217-1222 (2001).

(26) E. Baydoun, M. Karam, A. Wahab, M.S. Ahmed, M.S. Ahmad, C. Samreen et al., Microbial transformation of nandrolone with Cunninghamella echinulata and Cunninghamella blakesleeana and evaluation of leishmaniacidal activity of transformed products, Steroids, 88, 95-100 (2014).

(27) Sistema de Alerta tempranas: Detección de nuevas sustancias psicoactivas en Colombia. Bogotá D.C., Observatorio de drogas de Colombia, 2015.

(28) M. Meyer, P. Du, F. Schuster, H.H. Maurer, Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human livermicrosomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS, J. Mass Spectrom., 45(12), 1426-1442 (2010).

(29) E. Bertol, F. Mari, R.B. Berto, G. Mannaioni, F. Vaiano, D. Favretto, A mixed MDPV and benzodiazepine intoxication in a chronic drug abuser: Determination of MDPV metabolites by LC-HRMS and discussion of the case, Forensic Sci. Internai., 243, 149-155 (2014).

(30) B. Murray. C. Murphy, M. Beuhler, Death following recreational use of designer drug "bath salts" containing 3,4-methylenedioxypyrovalerone (MDPV), J. Med. Toxicol., 8(1), 69-75 (2012).

(31) C. Xueguo, Simultaneous determination of four designer drugs and their major-metabolites by liquid chromatography-mass spectrometry, J. Chromatogr., 992, 1-7 (2015).

(32) R. Brenneisen, S. Geisshusler, X. Shorno, Metabolism of cathinone to (-)-norephedrine and (-)-norpseudoephedrine, J. Pharm. Pharmacol., 38, 298-300 (1986).

(33) D. M. Mueller, K. M. Rentsch, Generation of metabolism by an automated online metabolism method using human liver microsomes with subsequent identification by LC-MS(n), and metabolism of 11 cathinones. Anal. Bioanal. Chem, 402(6), 2141-2151 (2012).

(34) R. López-Arnau, J. Martínez-Clemente, M. Carbó, D. Pubill, E. Escubedo, J. Camarasa, An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as "bath salts", Prog. Neuro-Psychoph., 45, 64-72 (2013).

(35) C.E. Cerniglia, J.B. Sutherland, S.A. Crow, Fungal metabolism of aromatic hydrocarbons. En: "Microbial Degradation of Natural Products", Editado por: G. Winkelmann G., VCH, Weinheim, 1992, p. 193-217.

(36) M. Hezari, P.J. Davis, 9 Models of mammalian metabolism: N-demethylation of furosemide to yield the mammalian metabolite CSA using Cunninghamella, DrugMetab., 20, 882-888 (1992).

(37) D. Zhang, Y. Yang, J. Leakey, C. Cerniglia, Phase I and phase II enzymes produced by Cunninghamella: Elegans for the metabolism of xenobiotics, FEMS Microbiol. Lett., 221-226 ( 1996).

(38) R.V. Smith, J.P. Rosazza, Microbial models of mammalian metabolism. Aromatic hydroxylation, Arch. Biochem. Biophys., 161(2), 551-558 (1974).

(39) R. Azerad, Microbial models for drug metabolism, Adv. Biochem. Engineer./Biotechnol., 63, 169-218 (1999).

(40) C.D. Murphy, Drug metabolism in microorganisms. Biotechnol. Lett., 37 19-28(2015).

(41) S. Asha, M. Vidyavathi, Cunninghamella: a microbial model for drug metabolism studies: A review, Biotechnol. Adv., 27, 16-29 (2009).

(42) R.E. Betts, D.E. Walters, J.P. Rosazza, Microbial transformations of antitumor compounds. 1. Conversion of acronycine to 9-hydroxyacronycine by Cunninghamella echinulata, J. Med. Chem, 17, 599-602 (1974).

(43) D. Zhang, F.E. Evans, J.P. Freeman, Y. Yang, J. Deck, C.E. Cerniglia, Formation of mammalian metabolites of cyclobenzaprine by the fungus, Cunninghamella elegans, Chem.-Biol. Interact., 102, 79-92 (1996).

(44) B.C. Foster, R.T. Coutts, F.M. Pasutto, A. Mozayani, Microbial metabolism of phenelzine and pheniprazine, Life Sciences, 42, 285-292 (1988).

(45) D. Zhang, F.E. Evans, J.P. Freeman, B. Duhart, C.E. Cerniglia, Biotransformation of amitriptyline by Cunninghamella elegans. Drug metabolism and disposition: the biological fate of chemicals, DrugMetab. Dispos., 23, 1417-1425 (1995).

(46) D. Zhang, Y. Yang, J.E. Leakey, C.E. Cernigli, Phase I and phase II enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics, FEMS Microbiol. Lett., 138, 221-226 (1996).

(47) Y.Z. Zhu, Y.S. Keum, L. Yang, H. Lee, H. Park, J.H. Kim, Metabolism of a fungicide mepanipyrim by soil fungus Cunninghamella elegans ATCC 36112, J. Agricult. Food Chem., 58, 12379-12384 (2010).

(48) S. Asha, M. Vidyavathi, Cunninghamella - A microbial model for drug metabolism studies - A review, Biotechnol. Adv., 27, 16-29 (2009).

(49) D. Zhang, F.E. Evans, J.P. Freeman, Y. Yang, J. Deck, C.E. Cerniglia, Formation of mammalian metabolites of cyclobenzaprine by the fungus, Cunninghamella elegans, Chem.-Biol. Interact., 102, 79-92 (1996).

(50) D. Zhang, F.E. Evans, J.P. Freeman, B. Duhart, C.E. Cerniglia, Biotransformation of amitriptyline by Cunninghamella elegans, Drug Metab. Dispos., 23, 14171425 (1995).

(51) J.D. Moody, J.P. Freeman, P.P. Fu, C.E. Cerniglia, Biotransformation of mirtazapine by Cunninghamella elegans, Drug Metab. Dispos., 30, 1274-1279 (2002).

(52) B. Ma, H.H. Huang, X.Y. Chen, Y.M. Sun, L.H. Lin, D.F. Zhong, Biotransformation of metoprolol by the fungus Cunninghamella blakesleeana, Acta Pharmacol. Sin., 28 1067-1074 (2007).

(53) J.D. Moody, D. Zhang, T.M. Heinze, C.E. Cerniglia, Transformation of amoxapine by Cunninghamella elegans, Appl. Environ. Microbiol., 66, 3646-3649 (2000).

(54) J.D. Moody, J.P. Freeman, C.E. Cerniglia, Biotransformation of doxepin by Cunninghamella elegans, Drug Metab. Dispos., 27, 1157-1164 (1999).

(55) D. Zhang, J.P. Freeman, J.B. Sutherland, A.E. Walker, Y. Yang, C.E. Cerniglia, Biotransformation of chlorpromazine and methdilazine by Cunninghamella elegans, Appl. Environ. Microbiol., 62, 798-803 (1996).

(56) D. Zhang, E.B. J.R. Hansen, J. Deck, T.M. Heinze, A. Henderson, W.A. Korfmacher, C.E. Cerniglia, Fungal transformations of antihistamines: Metabolism of cyproheptadine hydrochloride by Cunninghamella elegans, Xenobiotica, 27 301-315 (1997).

(57) C.E. Cerniglia, S.K. Yang, Stereoselective metabolism of anthracene and phenanthrene by the fungus Cunninghamella elegans, Appl. Environ. Microbiol., 47, 119-124 (1984).

(58) J.V. Pothuluri, J.P. Freeman, F.E. Evans, C.E. Cerniglia, Fungal metabolism of acenaphthene by Cunninghamella elegans, Appl. Environ. Microbiol., 58, 3654-3659 (1992).

(59) C.E. Cerniglia, D.T. Gibson, Metabolism of naphthalene by Cunninghamella elegans, Appl. Environ. Microbiol., 34, 363-370 (1977).

(60) C.E. Cerniglia, K.J. Lambert, D.W. Miller, J.P. Freeman, Transformation of 1-and 2-methylnaphthalene by Cunninghamella elegans, Appl. Environ. Microbiol., 47, 111-118 (1984).

(61) C.E. Cerniglia, P.P. Fu, S.K. Yang, Metabolism of 7-methylbenz[a]anthracene and 7-hydroxymethylbenz[a]anthracene by Cunninghamella elegans, Appl. Environ. Microbiol., 44, 682-689 (1982).

(62) S. Watanabe, U. Kuzhiumparambil, Z. Winiarski, S. Fu. Biotransformation of synthetic cannabinoids JWH-018, JWH-073 and AM2201 by Cunninghamella elegans, Forensic Sci. Internat., 261, 33-42 (2016).

(63) Y.Z. Zhu, Y.S. Keum, L. Yang, H. Lee, H. Park, J.H. Kim, Metabolism of a fungicide mepanipyrim by soil fungus Cunninghamella elegans ATCC36112, J. Agricult. Food Chem, 58, 12379-12384 (2010).

(64) M. Hangler, B. Jensen, S Ronhede, S.R. Sorensen, Inducible hydroxylation and demethylation of the herbicide isoproturon by Cunninghamella elegans, FEMS Microbiol. Lett., 268, 254-260 (2007).

(65) J.V. Pothuluri, F.E. Evans, D.R. Doerge, M.I. Churchwell, C.E. Cerniglia, Metabolism of metolachlor by the fungus Cunninghamella elegans, Arch. Environ. Contaminat. Toxicol., 32, 117-125 (1997).

(66) D. Zhang, Y. Yang, J.E. Leakey, C.E. Cerniglia, Phase I and phase II enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics, FEMS Microbiol. Lett, 138, 221-226 (1996).

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Silva, E. A., & Martínez, J. A. (2016). Antecedentes del estudio metabólico de MDPV y metilona. Propuesta de un modelo de biotransformación a través de hongos del género Cunninghamella. Revista Colombiana De Ciencias Químico-Farmacéuticas, 45(3), 484-502. https://doi.org/10.15446/rcciquifa.v45n3.62055

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