Importance of P-glycoprotein at blood–tissue barriers

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Abstract

P-glycoprotein is the product of the ABCB1 [also known as multidrug resistance 1 (MDR1)] gene. It translocates a broad variety of xenobiotics out of cells. P-glycoprotein was first described in tumor cells that were resistant to various anticancer agents as a result of P-glycoprotein overexpression. P-glycoprotein is not only expressed in tumor cells but also in a broad variety of normal tissues with excretory function (small intestine, liver and kidney) and at blood–tissue barriers (blood–brain barrier, blood–testis barrier and placenta). In particular, following the generation of P-glycoprotein-deficient mice it became clear that this efflux transporter limits the absorption of orally administered drugs, promotes drug elimination into bile and urine, and protects various tissues (e.g. brain, testis and fetus) from potentially toxic xenobiotics. In humans, a considerable interindividual variability in P-glycoprotein tissue expression is observed, and current research is focused on the potential role of ABCB1 polymorphisms and haplotypes that affect P-glycoprotein tissue expression, plasma concentrations of drugs, the frequency of adverse drug reactions and treatment outcome.

Section snippets

Intestinal P-glycoprotein and bioavailability

Traditionally, drug absorption was considered as a passive process. Major factors that affect drug absorption from the gut lumen are physicochemical properties of the drug (e.g. pKa, molecular weight, lipophilicity and solubility) and biological factors (e.g. gastric and intestinal transit time, luminal pH and mucosal blood flow) [13]. However, enterocytes, like hepatocytes, simultaneously express the major drug-metabolizing enzyme CYP3A4 and the efflux transporter P-glycoprotein [14]. This

P-glycoprotein and the blood–brain barrier

The blood–brain barrier is an important interface between blood and brain that is formed by endothelial cells lining the brain capillaries [36], and is thought to protect the brain from xenobiotics and regulate brain homeostasis (Figure 1). Similar to drug absorption from the gut lumen, physicochemical properties of drugs (e.g. lipophilicity) determine the extent of passive drug translocation across the blood–brain barrier. Passive paracellular transport of hydrophilic compounds is restricted

P-glycoprotein and the maternal–fetal barrier

Another important blood–tissue barrier is the maternal–fetal interface. Similar to the other organs discussed earlier, the placenta expresses multiple drug transporters, including P-glycoprotein (Figure 1) 43, 44. These transporters are again assumed to contribute to protecting the fetus after unintentional exposure of the mother to xenobiotics or a required drug therapy of the mother during pregnancy. In accordance with this hypothesis, Smit et al. [45] showed that after intravenous

P-glycoprotein and HIV

Drug penetration through blood–tissue barriers influences the treatment of HIV in several ways. As mentioned earlier, intestinal P-glycoprotein has been shown to limit the absorption of HIV protease inhibitors [8]. Moreover, data from animal models indicate that P-glycoprotein expressed in the blood–brain barrier limits access of HIV protease inhibitors to the brain, thereby possibly contributing to virus persistence in this sanctuary site 8, 41. Finally, P-glycoprotein is also expressed in

ABCB1 polymorphisms

The role of ABCB1 genetic polymorphisms or haplotypes on P-glycoprotein expression, plasma concentrations of P-glycoprotein substrates, treatment outcome, drug-induced toxicity and disease risk is an area of intensive and active research. Present knowledge is summarized in recent review articles 54, 55, 56. P-glycoprotein expression shows pronounced interindividual differences in various tissues (e.g. small intestine and liver) 23, 57. It appears that the effects of ABCB1 polymorphisms and

Concluding remarks

An appreciation of the role of P-glycoprotein in drug disposition and effects has considerably improved our understanding of drug handling in humans. However, multiple additional uptake [e.g. organic anion transporting polypeptide C [OATP-C (also known as SLC21A6 and SLC01B1)] for pravastatin] and efflux transporters (e.g. the MRP family for drug conjugates) exist in all the tissues discussed. For example, recent data indicate that polymorphisms in the gene encoding the OATP-C uptake

Acknowledgements

My work cited in this article is supported by grants of the Deutsche Forschungsgemeinschaft (FR 1298/2–3; Bonn, Germany) and the Robert Bosch Foundation (Stuttgart, Germany).

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