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

Retapamulin, a semi-synthetic 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 tri-hydroxylation and demethylation. Like tiamulin and valnemulin, the major metabolic routes of retapamulin were hydroxylation at the 2β and 8α positions of the mutilin moiety. Moreover, in vivo metabolism concurred with the results of the in vitro assays. Additionally, we observed the significant inter-species metabolic differences of retapamulin. Until now, modifying the side chain was the mainstream 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 enzymes inhibitor to be promising pathways in the development of novel pleuromutilins drugs with slow metabolism and long efficacy.

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