Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier

Demeule, Michel; Régina, Anthony; Jodoin, Julie; Laplante, Alain; Dagenais, Claude; Berthelet, France; Moghrabi, Albert; Béliveau, Richard

doi:10.1016/s1537-1891(02)00201-x

Cited by 202 publications

(134 citation statements)

References 86 publications

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“…10 The exact localization of Pgp in the BBB has been the object of numerous investigations using various experimental approaches such as in situ hybridization and immunohistochemistry. 21 There are two types of human Pgp: type I (also termed "MDR1 Pgp"), encoded by the MDR1 gene, which confers the drug resistance phenotype and drug efflux at the BBB (only this type will dealt with in this review); and type II, encoded by MDR2, present in the canalicular membrane of hepatocytes and functioning as a phosphatidylcholine translocase. 21 In rodents, the multidrug resistance type I Pgp is encoded by two genes (mdr1a, mdr1b).…”

mentioning

confidence: 99%

“…21 There are two types of human Pgp: type I (also termed "MDR1 Pgp"), encoded by the MDR1 gene, which confers the drug resistance phenotype and drug efflux at the BBB (only this type will dealt with in this review); and type II, encoded by MDR2, present in the canalicular membrane of hepatocytes and functioning as a phosphatidylcholine translocase. 21 In rodents, the multidrug resistance type I Pgp is encoded by two genes (mdr1a, mdr1b). 21 The substrate specificity of mdr1a and mdr1b Pgp in the rodent is different but partly overlapping, and together the two rodent genes are expressed in roughly the same manner as the single human MDR1 gene, suggesting that they perform the same set of functions in rodents as the MDR1 Pgp in man.…”

mentioning

confidence: 99%

“…21 In rodents, the multidrug resistance type I Pgp is encoded by two genes (mdr1a, mdr1b). 21 The substrate specificity of mdr1a and mdr1b Pgp in the rodent is different but partly overlapping, and together the two rodent genes are expressed in roughly the same manner as the single human MDR1 gene, suggesting that they perform the same set of functions in rodents as the MDR1 Pgp in man. 10 Both mdr1a and mdr1b are present in rodent brain, but only mdr1a is localized in brain capillaries of mice and rats, whereas mdr1b is present only in brain parenchyma.…”

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confidence: 99%

“…10 Both mdr1a and mdr1b are present in rodent brain, but only mdr1a is localized in brain capillaries of mice and rats, whereas mdr1b is present only in brain parenchyma. 21 At the subcellular level, most of the published data demonstrate that Pgp [or the gene(s) encoding Pgp] are principally expressed at the luminal (apical) membrane of brain capillary endothelial cells in mammals, including humans (FIG. 1).…”

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confidence: 99%

“…1). 6,9,21 Thus, Pgp substrate drugs entering the endothelial cells from the blood are immediately pumped back into the blood. As a consequence, the net penetration of substrate drugs and other substrate compounds from the blood into the brain tissue can be dramatically decreased.…”

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Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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Summary:The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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Evaluation of the Collective Impact of Passive Permeability and Active Transport on In Vivo Blood‐Brain Barrier and Gastrointestinal Drug Absorption

Volpe¹,

Shen²,

Balimane³

2014

Predictive ADMET

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Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease

Rabiee

Ahmadi

Afshari

et al. 2020

Advanced Therapeutics

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Currently, Alzheimer's disease (AD) accounts for more than half of all dementia cases. Although genetics, age, and environmental factors affect the disease, the cause of AD is not yet fully known. Various drugs have been proposed for the prevention and treatment of AD, but the delivery of these therapeutic agents to the brain is difficult. The blood-brain barrier prevents systemic drugs from accessing the central nervous system and designing a suitable system to overcome this barrier has attracted much attention. The intranasal pathway, given its proximity to the brain, provides a great opportunity for drug delivery. Understanding the physiological characteristics of the nose can be useful in selecting the appropriate carrier and material. Some of the emerging vehicles used for nose-to-brain delivery of anti-AD drugs are natural (such as chitosan) and polymeric (such as poly(lactic-co-glycolic acid) and polyethylene glycol) nanoparticles (NPs). This review discusses the hypotheses for AD pathogenesis and highlights recent advances in the applications of natural and polymeric NPs for treatment. The fundamental and applied aspects of this approach for nasal drug delivery to the brain are reviewed here with thoughts on what is needed for the field to mature also provided.

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Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier

Cited by 202 publications

References 86 publications

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

Evaluation of the Collective Impact of Passive Permeability and Active Transport on In Vivo Blood‐Brain Barrier and Gastrointestinal Drug Absorption

Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease

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