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J Pharm Sci. 2017 Sep;106(9):2257-2264. doi: 10.1016/j.xphs.2017.04.022. Epub 2017 Apr 21.

A Critical View on In Vitro Analysis of P-glycoprotein (P-gp) Transport Kinetics.

Author information

1
Bioneer-FARMA, Department of Pharmacy, Universitetsparken 2, Copenhagen DK-2100, Denmark.
2
Section of Pharmaceutical Design and Drug Delivery, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark. Electronic address: birger.brodin@sund.ku.dk.

Abstract

Transport proteins expressed in the different barriers of the human body can have great implications on absorption, distribution, and excretion of drug compounds. Inhibition or saturation of a transporter can potentially alter these absorbtion, distribution, metabolism and elimination properties and thereby also the pharmacokinetic profile and bioavailability of drug compounds. P-glycoprotein (P-gp, ABCB1) is an efflux transporter which is present in most of the barriers of the body, including the small intestine, the blood-brain barrier, the liver, and the kidney. In all these tissues, P-gp may mediate efflux of drug compounds and may also be a potential site for drug-drug interactions. Consequently, there is a need to be able to predict the saturation and inhibition of P-gp and other transporters in vivo. For this purpose, Michaelis-Menten steady-state analysis has been applied to estimate kinetic parameters, such as Km and Vmax, for carrier-mediated transport, whereas half-maximal inhibitor concentration (IC50) and the disassociation constant for an inhibitor/P-gp complex (Ki) have been determined to estimate P-gp inhibition. This review addresses in vitro methods commonly used to study P-gp transport kinetics and aims at providing a critical evaluation of the application of steady-state Michaelis-Menten analysis of kinetic parameters for substrate/P-gp interactions.

KEYWORDS:

ABC transporters; ADME; Michaelis–Menten kinetics; P-glycoprotein; drug interactions; drug transport; in vitro models

PMID:
28438535
DOI:
10.1016/j.xphs.2017.04.022
[Indexed for MEDLINE]

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