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Unravelling the metabolic routes of retapamulin : insights into drug development of pleuromutilins

Author
Organization
Abstract
Retapamulin, a semisynthetic pleuromutilin derivative, is exclusively used for the topical short-term medication of impetigo and staphylococcal infections. In the present study, we report that retapamulin is adequately and rapidly metabolized in vitro via various metabolic pathways, such as hydroxylation, including mono-, di-, and trihydroxylation, and demethylation. Like tiamulin and valnemulin, the major metabolic routes of retapamulin were hydroxylation at the 2 beta and 8 alpha positions of the mutilin moiety. Moreover, in vivo metabolism concurred with the results of the in vitro assays. Additionally, we observed significant interspecies differences in the metabolism of retapamulin. Until now, modifying the side chain was the mainstream method for new drug discovery of the pleuromutilins. This approach, however, could not resolve the low bioavailability and short efficacy of the drugs. Considering the rapid metabolism of the pleuromutilins mediated by cytochrome P450 enzymes, we propose that blocking the active metabolic site (C-2 and C-8 motif) or administering the drug in combination with cytochrome P450 enzyme inhibitors is a promising pathway in the development of novel pleuromutilin drugs with slow metabolism and long efficacy.
Keywords
drug discovery and development, high-resolution mass spectrometry, metabolism, retapamulin, QUADRUPOLE/TIME-OF-FLIGHT, GRAM-POSITIVE PATHOGENS, IN-VITRO, ANTIBACTERIAL ACTIVITY, TIAMULIN METABOLITES, WOUND MICROBIOLOGY, VALNEMULIN, DERIVATIVES, PHARMACOKINETICS, RESISTANCE

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Chicago
Sun, Feifei, Huiyan Zhang, Gerard Gonzales, Jinhui Zhou, Yi Li, Jinzhen Zhang, Yue Jin, et al. 2018. “Unravelling the Metabolic Routes of Retapamulin : Insights into Drug Development of Pleuromutilins.” Antimicrobial Agents and Chemotherapy 62 (4).
APA
Sun, Feifei, Zhang, H., Gonzales, G., Zhou, J., Li, Y., Zhang, J., Jin, Y., et al. (2018). Unravelling the metabolic routes of retapamulin : insights into drug development of pleuromutilins. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 62(4).
Vancouver
1.
Sun F, Zhang H, Gonzales G, Zhou J, Li Y, Zhang J, et al. Unravelling the metabolic routes of retapamulin : insights into drug development of pleuromutilins. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2018;62(4).
MLA
Sun, Feifei, Huiyan Zhang, Gerard Gonzales, et al. “Unravelling the Metabolic Routes of Retapamulin : Insights into Drug Development of Pleuromutilins.” ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 62.4 (2018): n. pag. Print.
@article{8552994,
  abstract     = {Retapamulin, a semisynthetic pleuromutilin derivative, is exclusively used for the topical short-term medication of impetigo and staphylococcal infections. In the present study, we report that retapamulin is adequately and rapidly metabolized in vitro via various metabolic pathways, such as hydroxylation, including mono-, di-, and trihydroxylation, and demethylation. Like tiamulin and valnemulin, the major metabolic routes of retapamulin were hydroxylation at the 2 beta and 8 alpha positions of the mutilin moiety. Moreover, in vivo metabolism concurred with the results of the in vitro assays. Additionally, we observed significant interspecies differences in the metabolism of retapamulin. Until now, modifying the side chain was the mainstream method for new drug discovery of the pleuromutilins. This approach, however, could not resolve the low bioavailability and short efficacy of the drugs. Considering the rapid metabolism of the pleuromutilins mediated by cytochrome P450 enzymes, we propose that blocking the active metabolic site (C-2 and C-8 motif) or administering the drug in combination with cytochrome P450 enzyme inhibitors is a promising pathway in the development of novel pleuromutilin drugs with slow metabolism and long efficacy.},
  articleno    = {e02388-17},
  author       = {Sun, Feifei and Zhang, Huiyan and Gonzales, Gerard and Zhou, Jinhui and Li, Yi and Zhang, Jinzhen and Jin, Yue and Wang, Zhanhui and Li, Yanshen and Cao, Xingyuan and Zhang, Suxia and Yang, Shupeng},
  issn         = {0066-4804},
  journal      = {ANTIMICROBIAL AGENTS AND CHEMOTHERAPY},
  language     = {eng},
  number       = {4},
  pages        = {10},
  title        = {Unravelling the metabolic routes of retapamulin : insights into drug development of pleuromutilins},
  url          = {http://dx.doi.org/10.1128/aac.02388-17},
  volume       = {62},
  year         = {2018},
}

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