Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

Biochim Biophys Acta. 2000 Dec 15;1524(2-3):212-9. doi: 10.1016/s0304-4165(00)00160-4.

Abstract

The brain distribution of the enantiomers of the antimalarial drug mefloquine is stereoselective according to the species. This stereoselectivity may be related to species-specific differences in the properties of some membrane-bound transport proteins, such as P-glycoprotein (P-gp). The interactions of racemic mefloquine and its individual enantiomers with the P-glycoprotein efflux transport system have been analysed in immortalised rat brain capillary endothelial GPNT cells. Parallel studies were carried out for comparison in human colon carcinoma Caco-2 cells. The cellular accumulation of the P-glycoprotein substrate, [(3)H]vinblastine, was significantly increased both in GPNT cells and in Caco-2 cells when treated with racemic mefloquine and the individual enantiomers. In GPNT cells, the (+)-stereoisomer of mefloquine was up to 8-fold more effective than its antipode in increasing cellular accumulation of [(3)H]vinblastine, while in Caco-2 cells, both enantiomers were equally effective. These results suggest that racemic mefloquine and its enantiomers are effective inhibitors of P-gp. Furthermore, a stereoselective P-glycoprotein inhibition is observed in rat cells but not in human cells. The efflux of [(14)C]mefloquine from GPNT cells was decreased when the cells were incubated with the P-gp modulators, verapamil, cyclosporin A or chlorpromazine, suggesting that MQ could be a P-gp substrate.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Antimalarials / pharmacology*
  • Brain Chemistry*
  • Caco-2 Cells
  • Cell Line
  • Cerebrovascular Circulation
  • Cyclosporine / pharmacology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Mefloquine / pharmacology*
  • Rats
  • Stereoisomerism
  • Substrate Specificity

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antimalarials
  • Cyclosporine
  • Mefloquine