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Xenobiotica
the fate of foreign compounds in biological systems
Volume 47, 2017 - Issue 3
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Animal Pharmacokinetics and Metabolism

Isolation and identification of phase I metabolites of butyrolactone I in rats

, , , , , , & show all
Pages 236-244 | Received 17 Feb 2016, Accepted 26 Mar 2016, Published online: 08 Sep 2016
 

Abstract

1. Butyrolactone I (BL-I), one of the major secondary metabolites of fungus Aspergillus terreus, is a selective cdc2 kinase inhibitor. In the present study, the metabolism of BL-I in male Wistar rats was investigated by characterizing metabolites excreted into feces.

2. Following an oral dose of 40 mg/kg BL-I, 10 phase I metabolites were isolated from the feces of rats, and their structures were identified on the basis of a range of spectroscopic data and ICD analysis. These metabolites were fully characterized as butyrolactone VI (M1), aspernolide E (M2), 7′′S-hydroxy-9′′-ene-butyrolactone I (M3), 7′′R-hydroxy-9′′-ene-butyrolactone I (M4), 7″S, 8″R-dihydroxy-aspernolide E (M5), 7″R, 8″S-dihydroxy-aspernolide E (M6), 7″R-acetyl-8″S-hydroxy-aspernolide E (M7), 7″S-acetyl-8″R-hydroxy-aspernolide E (M8), 7″R-methoxy-8″S-hydroxy-aspernolide E (M9), butyrolactone V (M10), respectively. It is the first time to describe the metabolites of BL-I in vivo, and metabolites M3 to M9 are new compounds.

3. BL-I and metabolites M2 to M10 were evaluated for their antimicrobial activity and in vitro antiproliferative activities. Only M-3 and M-4 showed inhibitory effect against staphylococcus aureus both with MIC of 125 μg/ml. BL-I and metabolites M-4 and M-5 exhibited potent cancer cell growth inhibitory activities against HL-60 (human leukemia) cell lines with the IC50 values of 13.2, 28.8 and 35.7 μM, respectively.

4. On the basis of metabolites profile, a possible metabolism pathway for BL-I in rats has been proposed. This is the first systematic study on the phase I metabolites of BL-I.

Declaration of interest

The authors report no conflicts of interest. We thank National Natural Science Foundation of China (81502951) for financial support.

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