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


METHODS
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.


RESULTS
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.


CONCLUSIONS
The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.
Choong
Eva
E
University of Lausanne, Centre for Psychiatric Neurosciences, Department of Psychiatry, CHUV, Hospital of Cery, Prilly, Switzerland.
Dobrinas
Maria
M
Carrupt
Pierre-Alain
PA
Eap
Chin B
CB
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations