In Vitro and in Vivo Evaluation of Phenylbutenoid Dimers as Inhibitors of P-Glycoprotein
| Autor: | Ah Reum Han, Hee Jong Lim, Eun Kyoung Seo, Song Wha Chae, Jeong Yeon Rhie, Jung Hyun Park, Hwa Jeong Lee |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Paclitaxel ATPase Administration Oral Biological Availability Pharmaceutical Science Pharmacology Analytical Chemistry chemistry.chemical_compound Pharmacokinetics In vivo Cyclohexenes Drug Discovery Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein Molecular Structure biology Organic Chemistry Stereoisomerism In vitro Rats Bioavailability Complementary and alternative medicine chemistry Drug Resistance Neoplasm biology.protein Molecular Medicine Female Efflux |
| Zdroj: | Journal of Natural Products. 76:2277-2281 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/np4004917 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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