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Chrysosplenetin inhibits artemisinin efflux in P-gp-over-expressing Caco-2 cells and reverses P-gp/MDR1 mRNA up-regulated expression induced by artemisinin in mouse small intestine
- Source :
- Pharmaceutical Biology, Vol 55, Iss 1, Pp 374-380 (2017)
- Publication Year :
- 2017
- Publisher :
- Taylor & Francis Group, 2017.
-
Abstract
- Context: CYP3A4 and P-gp together form a highly efficient barrier for orally absorbed drugs and always share the same substrates. Our previous work revealed that chrysosplenetin (CHR) significantly augmented the rat plasma level and anti-malarial efficacy of artemisinin (ART), partially due to the uncompetitive inhibition effect of CHR on rat CYP3A. But the impact of CHR on P-gp is still unknown. Objective: The present study investigates whether CHR interferes with P-gp-mediated efflux of ART and elucidates the underlying mechanism. Materials and methods: P-gp-over-expressing Caco-2 cells were treated with ART (10 μM) or ART-CHR (1:2, 10:20 μM) in ART bidirectional transport experiment. ART concentration was determined by UHPLC-MS/MS method. Healthy male ICR mice were randomly divided into nine groups (n = 6) including negative control (0.5% CMC-Na solution, 13 mL/kg), ART alone (40 mg/kg), verapamil (positive control, 40 mg/kg), ART-verapamil (1:1, 40:40 mg/kg), CHR alone (80 mg/kg), ART-CHR (1:0.1, 40:4 mg/kg), ART-CHR (1:1, 40:40 mg/kg), ART-CHR (1:2, 40:80 mg/kg) and ART-CHR (1:4, 40:160 mg/kg). The drugs were administrated intragastrically for seven consecutive days. MDR1 and P-gp expression levels in mice small intestine were examined by performing RT-PCR and western blot analysis. ABC coupling ATPase activity was also determined. Results: After combined with CHR (1:2), Papp (AP-BL) and Papp (BL-AP) of ART changed to 4.29 × 10 − 8 (increased 1.79-fold) and 2.85 × 10 − 8 cm/s (decreased 1.24-fold) from 2.40 × 10 − 8 and 3.54 × 10 − 8 cm/s, respectively. Efflux ratio (PBA/PAB) declined 2.21-fold (p
Details
- Language :
- English
- ISSN :
- 13880209 and 17445116
- Volume :
- 55
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Pharmaceutical Biology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.3dc0cadc285f4503b7bd0ab737a1274a
- Document Type :
- article
- Full Text :
- https://doi.org/10.1080/13880209.2016.1241810