Trends in Pharmacological Sciences
Importance of P-glycoprotein at blood–tissue barriers
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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