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Research ArticleArticle

Extractive Biotransformation for Production of Metabolites of Poorly Soluble Compounds: Synthesis of 32-Hydroxy-rifalazil

Vadim V. Mozhaev, Lyudmila V. Mozhaeva, Peter C. Michels and Yuri L. Khmelnitsky
Drug Metabolism and Disposition October 2008, 36 (10) 1998-2004; DOI: https://doi.org/10.1124/dmd.108.021832
Vadim V. Mozhaev
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Lyudmila V. Mozhaeva
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Peter C. Michels
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Yuri L. Khmelnitsky
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Abstract

A novel reaction system was developed for the production of metabolites of poorly water-soluble parent compounds using mammalian liver microsomes. The system includes the selection and use of an appropriate hydrophobic polymeric resin as a reservoir for the hydrophobic parent compounds and its metabolites. The utility of the extractive biotransformation approach was shown for the production of a low-yielding, synthetically challenging 32-hydroxylated metabolite of the antibiotic rifalazil using mouse liver microsomes. To address the low solubility and reactivity of rifalazil in the predominantly aqueous microsomal catalytic system, a variety of strategies were tested for the enhanced delivery of hydrophobic substrates, including the addition of mild detergents, polyvinylpyrrolidone, glycerol, bovine serum albumin, and hydrophobic polymeric resins. The latter strategy was identified as the most suitable for the production of 32-hydroxy-rifalazil, resulting in up to 13-fold enhancement of the volumetric productivity compared with the standard aqueous system operating at the solubility limit of rifalazil. The production process was optimized for a wide range of reaction parameters; the most important for improving volumetric productivity included the type and amount of the polymeric resin, cofactor recycling system, concentrations of the biocatalyst and rifalazil, reaction temperature, and agitation rate. The optimized extractive biotransformation system was used to synthesize 32-hydroxy-rifalazil on a multimilligram scale.

Footnotes

  • This research was sponsored by ActivBiotics, Inc. (Lexington, MA).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.021832.

  • ABBREVIATIONS: MLM, mouse liver microsome; P450, cytochrome P450; HPLC, high-performance liquid chromatography; EtOAc, ethyl acetate.

    • Received April 9, 2008.
    • Accepted July 2, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (10)
Drug Metabolism and Disposition
Vol. 36, Issue 10
1 Oct 2008
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Research ArticleArticle

Extractive Biotransformation for Production of Metabolites of Poorly Soluble Compounds: Synthesis of 32-Hydroxy-rifalazil

Vadim V. Mozhaev, Lyudmila V. Mozhaeva, Peter C. Michels and Yuri L. Khmelnitsky
Drug Metabolism and Disposition October 1, 2008, 36 (10) 1998-2004; DOI: https://doi.org/10.1124/dmd.108.021832

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Research ArticleArticle

Extractive Biotransformation for Production of Metabolites of Poorly Soluble Compounds: Synthesis of 32-Hydroxy-rifalazil

Vadim V. Mozhaev, Lyudmila V. Mozhaeva, Peter C. Michels and Yuri L. Khmelnitsky
Drug Metabolism and Disposition October 1, 2008, 36 (10) 1998-2004; DOI: https://doi.org/10.1124/dmd.108.021832
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