Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein.
The pharmacological effects of a drug are highly dependent on the absorption, metabolism, elimination, and distribution of the drug. In the past few years it has become apparent that transport proteins play a major role in regulating the distribution, elimination and metabolism of some drugs. As a consequence of our new understanding of the influence of transport proteins on the pharmacokinetic and pharmacodynamic behavior of drugs, increasing attention has been focused on the potential for drug-drug interactions arising from interactions with drug transport proteins. The efflux transporter P-glycoprotein (P-gp) has received the most attention with regard to its role in restricting drug absorption and distribution and as a potential source for variability in drug pharmacokinetics and pharmacodynamics. This review will focus on the evaluation of drug candidates to assess the potential for drug interactions at the level of P-gp. We will discuss the role of P-gp in drug disposition, the biochemistry of P-gp efflux as it relates to model systems to study drug interactions with P-gp, and the implementation of P-gp assay models within the drug discovery process.
Hochman
Jerome H
JH
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. Jerome_Hochman@merck.com
Yamazaki
Masayo
M
Ohe
Tomoyuki
T
Lin
Jiunn H
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D001692:Biological Transport; D015780:Carbapenems / Q000378:metabolism; D002478:Cells, Cultured; D015195:Drug Design; D004347:Drug Interactions; D066298:In Vitro Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015780:Carbapenems; C108047:L 749345; D004364:Pharmaceutical Preparations