NDLI: Kinetic Analysis of P-Glycoprotein-Mediated Transport by Using Normal Human Placental Brush-Border Membrane Vesicles

Content Provider	Springer Nature Link
Author	Ushigome, Fumihiko Koyabu, riko Satoh, Shoji Tsukimori, Kiyomi Naka, Hitoo Nakamura, Takari Uchiumi, Takeshi Kuwa, Michihiko Ohtani, Hisakazu Sawada, Yasufumi
Copyright Year	2003
Abstract	Purpose. P-Glycoprotein (Pgp) plays an important role in drug disposition and excretion in various tissues such as the brain, intestine, and kidney. Moreover, we have demonstrated that Pgp is expressed on the brush-border membranes of trophoblast cells in the placenta and restricts drug transfer from the maternal circulation to the fetus. However, the transport kinetics of physiologically expressed Pgp has scarcely been investigated. Methods. In this study, we assessed the functional kinetics of transport mediated by Pgp that is physiologically expressed in normal tissue by using human placental brush-border membrane vesicles (BBMVs). Digoxin and vinblastine were used as typical substrates of Pgp. Results. The uptakes of [$^{3}$H]digoxin and [$^{3}$H]vinblastine into BBMVs were significantly increased in the presence of an ATP-regenerating system. The ATP-dependent uptakes of [$^{3}$H]digoxin and [$^{3}$H]vinblastine into BBMVs exhibited saturable kinetics. The Michaelis constants (K $_{t}$ values) were 2.65 ± 1.80 μM and 21.9 ± 3.37 μM, respectively. In the presence of a Pgp inhibitor such as verapamil, cyclosporine A, or progesterone, the ATP-dependent uptakes of [$^{3}$H]digoxin and [$^{3}$H]vinblastine into BBMVs were significantly reduced. Anti-Pgp monoclonal antibody C219 completely inhibited the uptake of [$^{3}$H]digoxin. Conclusions. The transport kinetics of [$^{3}$H]digoxin and [$^{3}$H]vinblastine by physiologically expressed Pgp were successfully evaluated by using BBMVs prepared from normal human placenta. The present method enabled us to evaluate the function of physiologically expressed Pgp and is superior to the use of cultured transfectants in terms of the yield of vesicles. The present method may also be applicable to investigating the influence of various factors such as the genotype of the MDR1 gene or various pathophysiologic states of neonates on the function of Pgp.
Starting Page	38
Ending Page	44
Page Count	7
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	20
Issue Number	1
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2003-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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