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Differential effect of P-gp and MRP2 on cellular translocation of gemifloxacin.

Abstract
Fluoroquinolones are broad spectrum antibiotics widely indicated in the treatment of both human and animal diseases. The primary objective of this study was to assess short and long term affinities of gemifloxacin towards efflux transporters (P-gp, MRP2) and nuclear hormone receptor (PXR). Uptake and dose dependent inhibition studies were performed with [(14)C] erythromycin (0.25 μCi/ml) on MDCKII-MDR1 and MDCKII-MRP2 cells. Cellular accumulation of calcein-AM was further determined to confirm the affinity of gemifloxacin towards P-gp and MRP2. Transport studies were conducted to determine bi-directional permeability and to assess efflux ratio of gemifloxacin. LS-180 cells were treated with three different concentrations of gemifloxacin for 72 h and real-time PCR analysis was performed to study the quantitative gene expression levels of PXR, MDR1 and MRP2. Further, [(14)C] erythromycin uptake was also performed on LS-180 treated cells to better delineate the functional activity of efflux transporters. Results from our study suggest that gemifloxacin may be a substrate of both the efflux transporters studied. This compound inhibited both P-gp and MRP2 mediated efflux of [(14)C] erythromycin in a dose dependent manner with IC(50) values of 123 ± 2 μM and 16 ± 2 μM, respectively. The efflux ratio of [(14)C] erythromycin lowered from 3.56 to 1.63 on MDCKII-MDR1 cells and 4.93 to 1.26 on MDCKII-MRP2 cells. This significant reduction in efflux ratio further confirmed the substrate specificity of gemifloxacin towards P-gp and MRP2. Long term exposure significantly induced the expression of PXR (18 fold), MDR1 (6 fold) and MRP2 (6 fold). A decrease (20%) in [(14)C] erythromycin uptake further confirmed the elevated functional activity of P-gp and MRP2. In conclusion, our studies demonstrated that gemifloxacin is effluxed by both P-gp and MRP2. Long term exposure induced their gene expression and functional activity. This substrate specificity of gemifloxacin towards these efflux transporters may be one of the major factors accounting for low oral bioavailability (71%). Better understanding of these mechanistic interactions may aid in the development of newer strategies to achieve adequate therapeutic levels and higher bioavailability.
AuthorsRamya Krishna Vadlapatla, Aswani Dutt Vadlapudi, Deep Kwatra, Dhananjay Pal, Ashim K Mitra
JournalInternational journal of pharmaceutics (Int J Pharm) Vol. 420 Issue 1 Pg. 26-33 (Nov 25 2011) ISSN: 1873-3476 [Electronic] Netherlands
PMID21864659 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2011 Elsevier B.V. All rights reserved.
Chemical References
  • ABCB1 protein, human
  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Bacterial Agents
  • Fluoresceins
  • Fluoroquinolones
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Naphthyridines
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Steroid
  • calcein AM
  • Erythromycin
  • Adenosine Triphosphate
  • Gemifloxacin
Topics
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
  • Adenosine Triphosphate (metabolism)
  • Animals
  • Anti-Bacterial Agents (metabolism, pharmacology)
  • Binding, Competitive
  • Biological Transport
  • Cell Line
  • Cell Membrane Permeability
  • Dogs
  • Dose-Response Relationship, Drug
  • Erythromycin (metabolism)
  • Fluoresceins (metabolism)
  • Fluoroquinolones (metabolism, pharmacology)
  • Gemifloxacin
  • Gene Expression Regulation
  • Humans
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
  • Naphthyridines (metabolism, pharmacology)
  • Pregnane X Receptor
  • RNA, Messenger (metabolism)
  • Real-Time Polymerase Chain Reaction
  • Receptors, Steroid (metabolism)
  • Time Factors
  • Transfection

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