Bi-directional transport studies in SimBioDASRTM and Caco-2 cells were employed to examine the transport profiles of Buph, Ligs and SenA. Apical to basolateral (A-B) transport studies of the tested compounds revealed high intestinal permeability and predicted human absorption of over 98%. Permeability ratio of B-A/A-B of Buph (0.7-1.3) and Ligs (0.8-1.2) indicated that they were transported by passive transcellular and paracellular pathways while the low B-A/A-B ratio of SenA may imply possible involvement of other transport mechanisms. One metabolite (M-1) generated from hydration of Buph was observed in Caco-2 cells and the fraction of metabolism was 12.5% (A-B). / In conclusion, Buph, Ligs and SenA were predicted to have good intestinal absorptions in human and rat. However, extensive hepatic and intestinal first-pass metabolism of Buph in rat and human were found to cause its low oral bioavailability. On the other hand, certain degree of hepatic first-pass metabolism of Ligs and SenA may account for the partial loss of drugs via oral administration to rat. Therefore, other routes of delivery, such as sublingual administration, are worth to be considered to improve the therapeutic effects of chuanxiong. / In the rat SPIP, permeability calculated from the appearance of Buph in mesenteric blood (Pblood) was 6.0+/-1.7 x 10-4 cm/s while the fraction of formation of M-1 was about 7.1%. Together with the in vitro results, it is proposed that first-pass metabolism of Buph was present in human and rat small intestine. Moreover, Ligs and SenA had high Pblood values of 4.2+/-1.2 x 10-3 cm/s and 3.8+/-2.8 x 10-3 cm/s, respectively, indicated that they were highly permeable across rat intestinal mucosa. No metabolism of Ligs was observed. But several metabolites of SenA were detected despite they were not quantified in the present study. / In vitro metabolic studies of Buph demonstrated that major metabolite M-1, which was also found in Caco-2 cells and SPIP, formed mainly in intestine and liver cytosol in rat and human. The intrinsic clearance (Vmax/Km) of Buph was extensive and similar in both organs, and its extent in human was comparable to that in rat. The sum of the estimated in vivo extraction ratio of Buph by liver (48.3%) and intestine (55.0%) was higher the loss via oral administration to rat (77%). On the other hand, several metabolites of Ligs and SenA were found in rat and human liver microsome but not in intestinal preparations. The estimated in vivo extraction ratio by liver of rat was 47.3% (Ligs) and 22.9% (SenA), respectively, which were less than the corresponding loss via oral administration to rat (Ligs: 92.2% and SenA: 97.7%), suggesting that first-pass effect other than metabolism of these two compounds in intestine also contributed to their low oral bioavailability. / Rhizoma chuanxiong is commonly prescribed orally for improving blood circulation and treating cardiovascular disorders in China. Like other traditional Chinese medicines, chuanxiong has been used for thousands of years in China but its chemical basis, pharmacological effects and pharmacokinetic fates of the active ingredients, especially absorption, are poorly understood. Recently, seventeen compounds such as 3-butylidenephthalide (Buph), Z-ligustilide (Ligs), senkyunolide A (SenA), vanillin (Vani), ferulic acid (Fera), senkyunolide I (SenI), senkyunolide H (SenH), coniferyl ferulate (ConFer), sedanolide (Sdan), riligustilide (Rili) and levistolide A (LevA) have been isolated and recognized as the main constituents of chuanxiong by our research team (Li et al., 2003). Moreover, it has been demonstrated that Buph, Ligs and SenA are bioactive components of chuanxiong for vasodilatation and anti-thromboembolism (Chan, 2005) though their oral bioavailability in rat are very low (2.3, 7.8 and 23% respectively) (Yan, 2005). Therefore, the present study aims at investigating the intestinal permeability of the major ingredients of chuanxiong and characterizing the intestinal absorption and first-pass metabolism of Buph, Ligs and SenA by in vitro Caco-2 cell monolayers, SimBioDASRTM , in situ single-pass intestinal perfusion (SPIP) in rat and in vitro metabolism using rat and human intestine and liver subcellular fractions respectively. / Using the in vitro cell monolayers of SimBioDAS RTM, the intestinal permeability of major components of chuanxiong ranged from 12.2+/-1.6 x 10-6 cm/s to 70.6+/-9.6 x 10-6 cm/s with a rank order of Fera < Buph < Ligs < Sdan < SenH < SenI < SenA < Vani. They were predicted to have over 70% absorption in human. However, ConFer, Rili and LevA were estimated to have poor human oral absorption. / Ko Nga Ling. / "September 2005." / Adviser: Ge Lin. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1577. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 215-239). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_343860 |
| Date | January 2005 |
| Contributors | Ko, Nga Ling., Chinese University of Hong Kong Graduate School. Division of Pharmacology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xxvii, 239 p. : ill.) |
| Coverage | China |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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