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).
References (79)
A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants
Biochim. Biophys. Acta
(1976)Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs
Cell
(1994)The multidrug resistance protein family
Biochim. Biophys. Acta
(1999)Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview
Adv. Drug Deliv. Rev
(2003)The barrier function of CYP3A4 and P-glycoprotein in the small bowel
Adv. Drug Deliv. Rev
(1997)The drug efflux–metabolism alliance: biochemical aspects
Adv. Drug Deliv. Rev
(2001)Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine
Eur. J. Pharm. Sci
(2000)Nuclear response elements mediate induction of intestinal MDR1 by rifampin
J. Biol. Chem
(2001)Drug-drug interaction mediated by inhibition and induction of P-glycoprotein
Adv. Drug Deliv. Rev
(2003)Drug transfer through mucus
Adv. Drug Deliv. Rev
(2001)
Blood–brain barrier function of P-glycoprotein
Adv. Drug Deliv. Rev
Human MDR1 and mouse mdr1a P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene
Arch. Biochem. Biophys
Efflux transporters of the human placenta
Adv. Drug Deliv. Rev
Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice
Reprod. Toxicol
P-glycoprotein expression and function in circulating blood cells from normal volunteers
Blood
Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study
Lancet
The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans
Adv. Drug Deliv. Rev
Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities
Biochem. Pharmacol
Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis
Gastroenterology
MDR1 Ala893 polymorphism is associated with inflammatory bowel disease
Am. J. Hum. Genet
Lack of association between the C3435T MDR1 gene polymorphism and inflammatory bowel disease in two independent Northern European populations
Gastroenterology
MDR1 gene polymorphism in ulcerative colitis
Gastroenterology
Cellular localization of the multidrug-resistance gene product P- glycoprotein in normal human tissues
Proc. Natl. Acad. Sci. U. S. A
Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues
J. Histochem. Cytochem
Drug transporters in HIV therapy
Top. HIV Med
Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A
J. Clin. Invest
P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs
J. Clin. Invest
The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors
J. Clin. Invest
Transporters and renal drug elimination
Annu. Rev. Pharmacol. Toxicol
Drug uptake systems in liver and kidney
Curr. Drug Metab
Role of P-glycoprotein in pharmacokinetics: clinical implications
Clin. Pharmacokinet
Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy
Mol. Carcinog
The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein
Clin. Pharmacokinet
P-glycoprotein increases from proximal to distal regions of human small intestine
Pharm. Res
The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions
J. Clin. Invest
The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux
Nat. Med
Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens
Clin. Pharmacol. Ther
Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine
Circulation
Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein
Br. J. Pharmacol
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