Drug transporters: Gatekeepers controlling access of xenobiotics to the cellular interior

Abstract

In this paper, we evaluate methodologies and null mouse models used to study drug transporter function in vitro and in vivo. P-glycoprotein and MRP null mice have been used to examine many aspects of xenobiotic distribution and bioavailability. Their advantage over conventional models is that they allow the exclusion of transporters from a particular process; however, they cannot be used to study the activity of the transporter that has been deleted. Use of humanized mice permits a logical progression from phenomena in wild-type mice via the effects of removing the mouse transporter to the consequences of replacing it with its human counterpart.

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

“…Overexpression of mdr1 has been shown in refractory ovarian cancer tumor cells (22). P-gp is capable of transporting a variety of substrates ranging in size from 300 to 2,000 Da (20). Cancer cells exhibiting upregulation of P-gp become resistant to multiple structurally and mechanistically unrelated chemotherapeutic agents and are classified as multidrug resistant (21).…”

“…Alternatively, drug delivery to tumor cells can be hindered by upregulation of cell membrane drug efflux transporters. Members of the adenosine triphosphate-binding cassette (ABC) transporter superfamily have been associated with drug resistance by decreasing the intracellular accumulation of hydrophobic chemotherapeutics (20). Of these, the product of the multidrug resistance 1 (mdr1) gene, P-glycoprotein (P-gp), is one of the key molecules leading to cancer multidrug resistance (21).…”

The Blood Brain Barrier — Regulation of Fatty Acid and Drug Transport

“…This is in contrast to studies by Roberts et al [116] suggesting MRP1 has a basolateral (abluminal) plasma membrane localization in rat brain microvessels. As MRP1 shows high transporter activity for conjugated compounds such as estradiol 17β glucuronides [117], it is interesting to note that Sugiyama and colleagues [118] demonstrated a reduction in elimination of estradiol 17β glucuronide from the brain of Mrp1 knockout mice compared to that observed in the wild-type controls with functional MRP1. These functional studies support the luminal expression of MRP1 and suggest a role in limiting brain exposure to drugs and endogenous solutes.…”

The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

“…Monolayers of immortalized cell lines (CaCo-2, LLC-PK1, and MDCKII) expressing human transporters and primary cell cultures (brain microvascular endothelial cells) serve as an efficient tool for screening transporter activities at the BBB. [2][3][4] Several compounds interact with the efflux transporters in vitro but play a minor role in substrate efflux at the BBB in vivo. 5 On the contrary, some high passive permeability substrates such as verapamil, itraconazole, and ketoconazole are negative in the MDCKIIMDR1 assay but show a P-gp-dependent brain exposure in vivo.…”

“…2 It is important to distinguish if poor brain penetration of an investigational drug is due to poor passive permeability or to efflux by an apically located transporter. Monolayers of immortalized cell lines (CaCo-2, LLC-PK1, and MDCKII) expressing human transporters and primary cell cultures (brain microvascular endothelial cells) serve as an efficient tool for screening transporter activities at the BBB.…”