Biotransformation of metoprolol by the fungus Cunninghamella blakesleeana

Abstract

Aim: To investigate the biotransformation of metoprolol, a β1‐cardioselective adrenoceptor antagonist, by filamentous fungus, and to compare the parallels between microbial transformation and mammalian metabolism. Methods: Five strains of Cunninghamella (Celegans AS 3.156, Celegans AS 3.2028, C echinulata AS 3.2004, C blakesleeana AS 3.153 and AS 3.910) were screened for the ability to transform metoprolol. The metabolites of metoprolol produced by C blakesleeana AS 3.153 were separated and assayed by liquid chromatography‐tandem mass spectrometry (LC/MSn). The major metabolites were isolated by semipreparative HPLC and the structures were identified by a combination of LC/MSn and nuclear magnetic resonance analysis. Results: Metoprolol was transformed to 7 metabolites; 2 were identified as new metabolites and 5 were known metabolites in mammals. Conclusion: The microbial transformation of metoprolol was similar to the metabolism in mammals. The fungi belonging to Cunninghamella species could be used as complementary models for predicting in vivo metabolism and producing quantities of metabolite references for drugs like metoprolol.

Studies on the metabolism of five model drugs by fungi colonizing cadavers using LC-ESI-MS/MS and GC-MS analysis

“…repens and M. polycephala. This capability of C. elegans to produce a very wide range of human and/or fungal drug metabolites is in accordance with previous findings of other authors [22][23][24] and confirms the applicability of this C. elegans as a positive control organism in studies on fungal drug metabolism.…”

“…According to Ma et al [22], the common fragmentation pathways of MET and its metabolites can be interpreted as follows: neutral loss of the propyl moiety, and common neutral losses of isopropylamine and water (Fig. 3a-d).…”

“…Five fungal species previously reported to be present in or on corpses [14][15][16][17][18] and classified as risk I organisms by "Technical Rules for Biological Agents" in Germany, were selected as model organisms for the development of the in vitro model. Additionally, the fungus Cunninghamella elegans was used as an incubation control, as it has been widely employed in different models for mammalian drug metabolism [19][20][21][22][23][24][25].…”

The fungusCunninghamella eleganscan produce human and equine metabolites of selective androgen receptor modulators (SARMs)

“…The major phase II products were instead glucosides which have limited mammalian relevance. This was quite expected, since the glycosylation pathway has been previously described for C. elegans for many compound classes (Ma et al 2007).…”

“…In vitro metabolic models based on fungi could be useful alternatives to chemical synthesis and in vivo administration, as they are generally cheap, easy to handle, without ethical concerns and as the procedures are easily scalable (Zhang et al 1995;Pearce & Lushnikova 2006). A genus of fungi that has been investigated regarding drug biotransformation is Cunninghamella (Zhang et al 1995;Ma et al 2007;Tevell Åberg et al 2009Tevell Åberg et al , 2010Rydevik et al 2012). However, to the best of the authors' knowledge, the metabolism of arylpropionamide SARMs by Cunninghamella fungi has not been previously studied.…”