The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution

Abstract

Importance of the field: The permeability glycoprotein (P-gp) is an important protein transporter involved in the disposition of many drugs with different chemical structures, but few studies have examined a possible stereoselectivity in its activity. P-gp can have a major impact on the distribution of drugs in selected organs, including the brain. Polymorphisms of the ABCB1 gene, which encodes for P-gp, can influence the kinetics of several drugs.

Areas covered in this review: A search including publications from 1990 up to 2009 was performed on P-gp stereoselectivity and on the impact of ABCB1 polymorphisms on enantiomer brain distribution.

What the reader will gain: Despite stereoselectivity not being expected because of the large variability of chemical structures of P-gp substrates, structure–activity relationships suggest different P-gp-binding sites for enantiomers. Enantioselectivity in the activity of P-gp has been demonstrated by in vitro studies and in animal models (preferential transport of one enantiomer or different inhibitory potencies towards P-gp activity between enantiomers). There is also in vivo evidence of an enantioselective drug transport at the human blood-brain barrier.

Take home message: The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.

Keywords::

• ABCB1
• BBB
• chirality
• drug disposition
• drug transporters
• enantiomers
• genetic polymorphism
• isomer
• P-glycoprotein

Acknowledgement

E Choong and M Dobrinas contributed equally to this work.

Notes

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