title: An examination of the potential effect of lipids on the first-pass metabolism of the lipophilic drug anethol trithione.
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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Yu
authors.forename: Si-Fei
authors.initials: SF
authors.lastname: Han
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Chun-Liu
authors.initials: CL
authors.lastname: Zhu
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Gan
authors.forename: Yong
authors.initials: Y
authors.lastname: Gan
mesh_terms: D000781:Anethole Trithione / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000781:Anethole Trithione