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Stereoselective transport of hydrophilic quaternary drugs by human MDR1 and rat Mdr1b P‐glycoproteins
Author(s) -
Hooiveld Guido J E J,
Heegsma Janette,
Montfoort Jessica E van,
Jansen Peter L M,
Meijer Dirk K F,
Müller Michael
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704620
Subject(s) - p glycoprotein , chemistry , diastereomer , stereoselectivity , stereochemistry , vesicle , membrane , biochemistry , multiple drug resistance , catalysis , antibiotics
The present study was performed to evaluate and compare the ability of human MDR1 ‐, and rat Mdr1b ‐ and Mdr2 ‐P‐glycoproteins to transport hydrophilic monoquaternary drugs. Transport studies were performed with plasma membrane vesicles isolated from MDR1‐, Mdr1b‐, or Mdr2‐overexpressing insect cells. As model substrates we used the N ‐methylated derivatives of the diastereomers quinidine and quinine, the monoquaternary compounds N ‐methylquinidine and N ‐methylquinine. Vincristine, an established MDR1 substrate, was used as a reference. We observed ATP‐dependent uptake of all drugs studied into MDR1‐ and Mdr1b‐expressing vesicles. Mdr2 was not able to transport these compounds. MDR1‐ and Mdr1b‐mediated transport was saturable, and could be inhibited by various drugs, including PSC‐833. For both MDR1 and Mdr1b the V max / K m ratios (or clearance) of N ‐methylquinidine were greater than those determined for N ‐methylquinine. This stereoselective difference was also evident from differential inhibitory studies with the two isomers. Comparison of normalized clearance indicated that human MDR1 was more effective in transporting the tested substrates than rat Mdr1b. In conclusion, our results demonstrate that MDR1 and Mdr1b, but not Mdr2, are able to transport the monoquaternary model drugs; both MDR1 and Mdr1b display stereospecificity for these cations; and indicate human MDR1 is more efficient in transporting these cations than its rat orthologue Mdr1b.British Journal of Pharmacology (2002) 135 , 1685–1694; doi: 10.1038/sj.bjp.0704620