An examination of the potential effect of lipids on the first-pass metabolism of the lipophilic drug anethol trithione

Hong-Zhen Yu, Si-Fei Han, Ping Li, Chun-Liu Zhu, Xin-Xin Zhang, Li Gan, Yong Gan

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Abstract

In this study, an examination of the potential effect of lipids on the first-pass metabolism of anethol trithione (ATT) was investigated. ATT is metabolized rapidly and extensively in liver into 4-hydroxy-anethole trithione (ATX), which was confirmed using the rat intestinal perfusion with the mesenteric cannulation model. Male Sprague-Dawley rats were orally administered of the lipid-based formulations (prepared by medium chain triglycerides (MCT)), the cyclodextrin formulation and the suspension formulation, respectively. For 6.75 mg/kg groups, ATX/ATT area under the plasma concentration-time curve (AUC) ratio decreased by 87% and 76% after administration of the MCT-based formulations and the cyclodextrin formulation, when compared with the suspension formulation (p <0.05), respectively; for 2.25 mg/kg groups, it decreased by 53% in the MCT group when compared with the cyclodextrin group (p <0.05). The saturation of pre-system metabolism of ATT was observed after administration of the MCT-based formulations and the cyclodextrin formulation, likely as a result of enhanced absorption and therefore presentation of higher drug concentrations to liver, when compared with the suspension formulation. A trend toward lower systemic metabolite to parent ratios was evident after administration of the lipid formulations, when compared with the cyclodextrin formulation; however, this was not statistically significant. Further studies on the potential for lipids to inhibit hepatic metabolism are therefore warranted.
Original languageEnglish
Pages (from-to)5048-5058
Number of pages11
JournalJournal of Pharmaceutical Sciences
Volume100
Issue number11
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

Keywords

  • Anethol trithione
  • Dose proportionality
  • Drug metabolizing enzymes
  • First-pass metabolism
  • Formulation
  • Hepatic metabolism
  • Inhibition
  • Lipids
  • Medium chain triglycerides
  • Nonlinear pharmacokinetics

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