title: In vitro and in vivo evaluation of phenylbutenoid dimers as inhibitors of P-glycoprotein.
abstract: The expression of P-glycoprotein (P-gp), an ATP-dependent efflux transporter, is closely associated with the failure of chemotherapy and drug absorption. Two synthesized optically active phenylbutenoid dimers, 3S-(3,4-dimethoxyphenyl)-4R-{(E)-3,4-dimethoxystyryl}cyclohex-1-ene (1) and 3R-(3,4-dimethoxyphenyl)-4S-{(E)-3,4-dimethoxystyryl}cyclohex-1-ene (2), were tested for their P-gp inhibitory effects by measuring cellular accumulation and efflux of daunomycin in P-gp-overexpressed human breast cancer cells (MCF-7/ADR). Compound 2 significantly increased the accumulation of daunomycin (539%) and decreased the efflux of this compound (55.4%), and similar results were observed for 1. ATPase assays and Western blot analysis were performed to identify the mechanisms by which compounds 1 and 2 inhibit P-gp. In addition, changes in the pharmacokinetic profile of paclitaxel coadministered with 2 in rats were evaluated. Paclitaxel (25 mg/kg) when orally administered with 2 (5 mg/kg) improved its relative bioavailability by 185%. Compound 2 effectively improved cellular accumulation by reducing the efflux of daunomycin and significantly enhanced oral exposure to paclitaxel. Therefore, compound 2 may be useful for improving oral exposure and cellular availability of drugs that are also substrates of P-gp.
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences (Ewha Global Top 5 Program), Ewha Womans University , Seoul 120-750, Korea.
authors.forename: Song Wha
authors.initials: SW
authors.lastname: Chae
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Han
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Rhie
authors.forename: Hee-Jong
authors.initials: HJ
authors.lastname: Lim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Seo
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D053138:Cyclohexenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D013237:Stereoisomerism
chemical_list: C587213:3R-(3,4-dimethoxyphenyl)-4S-((E)-3,4-dimethoxystyryl)cyclohex-1-ene; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053138:Cyclohexenes; D017239:Paclitaxel