Rifampicin: biotransformation study using the fungus Cunninghamella elegans and monitoring through UHPLC-MS

Rafaela M. Sponchiado; Julia Sorrentino; Letícia M Cordenonsi; Alexandre M Fuentefria; Martin Steppe; Andreas Mendez; Cássia Virgínia Garcia

doi:10.22456/2527-2616.101989

Authors

Rafaela M. Sponchiado Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Julia Sorrentino Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Letícia M Cordenonsi Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Alexandre M Fuentefria Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Martin Steppe Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Andreas Mendez Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul
Cássia Virgínia Garcia Programa de Pós-graduação em Ciências Farmacêuticas - Universidade Federal do Rio Grande do Sul

DOI:

https://doi.org/10.22456/2527-2616.101989

Keywords:

biotransformation, new metabolite, rifampicin, Cunninghamella elegans, UHPLC-MS

Abstract

Drug biotransformation studies appear as an alternative to pharmacological investigations of metabolites, development of new drug candidates with reduced investment and most efficient production. The objective of this study was to evaluate the capacity of biotransformation of Rifampicin (RIF) by the filamentous fungus Cunninghamella elegans as a microbial model of mammalian metabolism. In 120 h, C. elegans transformed the drug into the following two metabolites: rifampicin quinone and novel metabolite. The products of rifampicin formed in vitro were monitored by HPLC-PDA, being identified through UHPLC–QTOF/MS. Metabolites were characterized according to their chromatographic profile, mass fragments and UV spectral data. The major metabolic pathways of rifampicin transformed by the fungus were oxidation, demethylation and mono-oxidation. The microbial transformation of RIF showed the potential of Cunninghamella species to produce RIF metabolites. This process can be used for a cost effective method for both known and unknown metabolite production.

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References

Zhang Y. The magic bullets and tuberculosis drug targets. Annu. Rev. Pharmacol Toxicol 2005; 45: 529-64.

Acocella G. Clinical pharmacokinetics of rifampicin. Clin Pharmacokinet 1978; 3: 108-127.

Drugbank, Rifampicin, 2017. Disponível em: https://www.drugbank.ca/drugs/DB01045 Acessed in 09.03.2019.

Mucklow JC. Martindale: The Complete Drug Reference. 36th Edition. London: Pharmaceutical Press, 2009.

Borges KB, Borges WDS, Pupo MT, Bonato PS. Endophytic fungi as models for the stereoselective biotransformation of thioridazine. Appl. Microbiol Biotechnol, 2007; 77: 669-674.

Adelin E, Servy C, Cortial S, Lévaique H, Gallard JF, Martin MT, et al. Biotransformation of natural compounds. Oxido-reduction of Sch-642305 by Aspergillus ochraceus ATCC 1009. Bioorg Med Chem Lett 2011; 21: 2456-2459.

Borges KB, De Souza Borges W, Durán-Patrón R, Pupo MT, Bonato PS, Collado IG. Stereoselective biotransformations using fungi as biocatalysts. Tetrahedron Lett 2009; 20: 385-397.

Molina G, Marostica MR, Pastore GM. Pseudomonas: A promising biocatalyst for the bioconversion of terpenes. Appl Microbiol Biotechnol 2013; 97: 1851–1864.

Asha S, Vidyavathi M. Cunninghamella – a microbial model for drug metabolism studies - a review. Biotechnol Adv 2009; 27: 16-29.

Srisailam K, Raj Kumar V, Veeresham C. Predicting drug interaction of Clopidogrel on microbial metabolism of Diclofenac. Appl Biochem Biotechnol 2010; 160: 1508-1516.

Barth T, Conti R, Puppo MT, Okano LT, Bonato PS. Chiral HPLC analysis of donepezil, 5-O-desmethyl donepezil and 6-O-desmethyl donepezil in culture medium: Application to fungal biotransformation studies. Anal Bioanal Chem 2012; 404: 257-266.

Quinn L, Dempsey R, Casey E, Kane A, Murphy CD. Production of drug metabolites by immobilised Cunninghamella elegans: from screening to scale up. J Ind Microbiol Biotechnol 2015; 42: 799-806.

Moody JD, Freeman JP, Fu PP, Cerniglia CE. Biotransformation of mirtazapine by Cunninghamella elegans. Drug Metab Dispos 2002; 30: 1274-1279.

Piska K, Żelaszczyk D, Jamrozik M, PEKALA E. Cunninghamella Biotransformation-Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process. Curr Drug Metab 2016; 17: 107-117.

Food and Drug Administration. Guidance: Bioanalytical Method Validation. 2013.

Prasad B, Singh S. In vitro and in vivo investigation of metabolic fate of rifampicin using an optimized sample preparation approach and modern tools of liquid chromatography–mass spectrometry. J Pharm and Biomedical Anal 2009; 50: 475-490.

Balbão MS, Bertucci C, Bergamaschi MM, Queiroz RHC, Malfará WR, Dreossi SAC, et al. Rifampicin determination in plasma by stir bar-sorptive extraction and liquid chromatography. J Pharm and Biomedical Anal 2010; 51: 1078-1083.

Li W, Wang J, Yan ZY. Development of a sensitive and rapid method for rifampicin impurity analysis using supercritical fluid chromatography. J Pharm and Biomedical Anal 2015; 114: 341-347.

Li J, Zhu M, Rajamani S, Uversky VN, Fink AL. Rifampicin inhibits α-synuclein fibrillation and disaggregates fibrils. Chem Biology 2004; 11: 1513- 1521.

Wang R, Cao WW, Khan AA, Cerniglia CE. Cloning, sequencing, and expression in Escherichia coli of a cytochrome P450 gene from Cunninghamella elegans. FEMS Microbiol Lett 2000; 188: 55-61.

Sorokoumova GM, Vostrikov VV, Selishcheva AA, Rogozhkina EA, Kalashnikova TYU, Shvets VI, et al. Bacteriostatic activity and decomposition products of rifampicin in aqueous solution and liposomal composition. Pharm Chem J 2008; 42: 35- 38.

Becker C, Dressman JB, Junginger HE, Kopp S, Midha KK, Shah VP, et al. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Rifampicin. J Pharma Sci 2009; 98: 2252-2267.