title: Xanthone analogues as potent modulators of intestinal P-glycoprotein.
abstract: Intestinal P-glycoprotein (P-gp) is a limiting step for oral absorption of drugs. Therefore, P-gp inhibitors have been studied as enhancers of oral absorption of drugs that are P-gp substrates. We investigated the in vitro and in vivo P-gp inhibitory activity of synthesized xanthone analogues. With 3-(3-chloro-2-hydroxypropoxy)-1-hydroxy-9H-thioxanthen-9-one, compound 13, accumulation of daunomycin (DNM) increased 707% and efflux of DNM decreased 66% compared to DNM alone. Relative bioavailability (RB) of paclitaxel (PTX, 25 mg/kg) increased 2.5-fold after oral administration with 13 (5 mg/kg). In a xenograft animal model, oral administration of PTX (40 mg/kg) with 13 (10 mg/kg) significantly inhibited tumour growth and was more effective than intravenously administered PTX (10 mg/kg) alone. Therefore, the synthesized xanthone analogue 13 might have therapeutic benefits for oral absorption of P-gp substrate anticancer drugs.
authors: College of Pharmacy (Global Top 5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors: Song Wha
authors: SW
authors: Chae
authors: Kolmar Korea Co., Ltd, 618-3 Sinjeong-ri, Yeongigun, Chungnam, Republic of Korea.
authors: Sangwook
authors: S
authors: Woo
authors: College of Pharmacy (Global Top 5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors: Jung Hyun
authors: JH
authors: Park
authors: College of Pharmacy (Global Top 5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors: Youngjoo
authors: Y
authors: Kwon
authors: College of Pharmacy, CHA University, Pocheon 487-010, Republic of Korea. Electronic address: yna7315@cha.ac.kr.
authors: Younghwa
authors: Y
authors: Na
authors: College of Pharmacy (Global Top 5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: hwalee@ewha.ac.kr.
authors: Hwa Jeong
authors: HJ
authors: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D065966:Absorption, Physicochemical; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D051381:Rats; D044004:Xanthones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D044004:Xanthones; C009689:xanthone
keywords: Bioavailability; P-glycoprotein inhibitor; Paclitaxel; Xanthone analogue; Xenograft