In vitro metabok stability and intestinal transport of P57AS3 (P57) from Hoodia gordonii and its interaction with drug metabolizing enzymes
In vitro metabok stability and intestinal transport of P57AS3 (P57) from Hoodia gordonii and its interaction with drug metabolizing enzymes
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DOI：
10.1055/s-2008-1074580
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发表时间：
2008-08-01
期刊：
影响因子：
2.7
通讯作者：
Khan, Shabana I.
中科院分区：
文献类型：
--
作者：
Madgula, Vamsi L. M.;Avula, Bharathi;Khan, Shabana I.
胡迪亚是一种生长在南非的多汁仙人掌状植物，因其抑制食欲的特性而被用于传统医学。它作为一种促进减肥的膳食补充剂最近得到了普及。据报道，氧孕烷甾体苷P57AS3 （P57）是负责厌氧活性的树液提取物的活性成分。关于其代谢稳定性、肠道转运和与药物代谢酶的相互作用尚无资料。本研究测定了P57在人肝微粒体中的代谢稳定性及其与药物代谢酶（CYP1A2、2C9、3A4和2D6）的相互作用。在Caco-2细胞肠道运输和吸收模型中研究P57的肠运输。P57在人肝微粒体存在下代谢稳定。该化合物抑制CYP3A4活性的IC50值为45 μ M，而对cyp1a2、2C9和2D6活性无抑制作用。在Caco-2模型中，P57在分泌方向上的转运高于吸收方向，在100和200 μ M时的外排比分别为3.1和3.8。多药耐药相关蛋白MRP1/MRP2 （MK-571）和P-gp（维拉帕米）的选择性抑制剂可抑制外排。综上所述，P57的肠道转运是由P-gp和MRP转运体介导的，该化合物代谢稳定，对CYP 3A4具有较弱的抑制作用。
Hoodia gordonii, a succulent cactus-like plant growing in South Africa, has been used in traditional medicine for its appetite suppressant properties. Its use as a dietary supplement to promote weight loss has recently gained popularity. An oxypregnane steroidal glycoside P57AS3 (P57) is reported to be the active constituent of the sap extract responsible for anorexigenic activity. No information is available about its metabolic stability, intestinal transport and interaction with drug metabolizing enzymes. In the present investigation, the metabolic stability of P57 in human liver microsomes and its interaction with drug metabolizing enzymes (CYP1A2, 2C9, 3A4 and 2D6) were determined. Intestinal transport of P57 was studied in the Caco-2 cell model of intestinal transport and absorption. P57 was metabolically stable in the presence of human liver microsomes. The compound inhibited CYP3A4 activity with an IC50 value of 45 mu M whereas the activity of CYP 1A2,2C9 and 2D6 was not inhibited. In the Caco-2 model, P57 exhibited a higher transport in the secretory direction than in the absorptive direction with efflux ratios of 3.1 and 3.8 at 100 and 200 mu M, respectively. The efflux was inhibited by selective inhibitors Of multidrug resistance associated proteins MRP1/MRP2 (MK-571) and P-gp (verapamil). In conclusion, intestinal transport of P57 was mediated by P-gp and MRP transporters, The compound was metabolically stable and showed weak inhibition of CYP 3A4.