Microbial production of phase I and phase II metabolites of propranolol

Abstract

1. The production in multimilligram amounts of 4- and 5-hydroxylated metabolites of (R)- or (S)-propranolol by biotransformation with two fungal strains, an Absidia sp. M50002 and a Cunninghamella sp. M50036, was carried out, starting from either the racemic drug or pure enantiomers.

2. While both enantiomers of propranolol were hydroxylated in the 5-position by incubation with strain M50002, the strain M50036 operated a chiral discrimination, resulting in the exclusive formation of the 4-hydroxy-(R)-enantiomer.

3. In addition, a Streptomyces sp. strain M52104, isolated from a soil sample, was selected for the high-yield regioselective β-glucuronidation of propranolol and its 4- and 5-hydroxylated derivatives.

4. NMR and mass spectroscopic data have been extensively used for the unambiguous characterization of 4- and 5-hydroxylated and glucuronidated derivatives, all of them corresponding to the major animal and human metabolites of propranolol, a typical substrate of CYP2D6.

Keywords::

• CYP2D6
• cytochrome P450-catalysed oxidations
• glucuronidation
• analytical methods
• metabolite identification
• drug metabolism
• regio- and stereoselective biotransformation

Acknowledgements

We are indebted to Gildas Bertho (UMR 8601 CNRS, Paris) for invaluable help in the NMR acquisitions and structural elucidations of metabolites.

Declaration of interest

The authors report no conflict of interest. All of the studies reported herein were supported by Bertin-Pharma. One of the authors (C. Marvalin) is employee of Bertin-Pharma. Part of this work was presented as a poster at the 9th International ISSX Meeting, September 4–8, 2010, Istanbul, Turkey and published as an abstract in the conference book.