Drug efflux transporters in the CNS

Sun, Haiying; Dai, Haiqing; Shaik, Naveed; Elmquist, William F.

doi:10.1016/s0169-409x(02)00172-2

Cited by 276 publications

(207 citation statements)

References 182 publications

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“…[7][8][9] Moreover, expression of this efflux transporter in certain tissue compartments such as the gastrointestinal tract and brain capillary endothelial cells limits oral absorption and CNS entry of many drugs. 7 The use of Pgp-expressing cell lines, the generation of Pgp knockout mice as well as studies using Pgp inhibitors in animals, contributed to a better understanding on the role of active transport processes for drug disposition.…”

Section: Introductionmentioning

confidence: 99%

“…8 In addition to Pgp, the ABC transporters of the multidrug resistance protein (MRP; ABCC) family and the breast cancer resistance protein (BCRP; ABCG2) have a role in drug disposition. 6,9 The family of mammalian ABC transporters, however, is far more extensive, and functionally highly diverse. 1 In this review, we limit ourselves to the following ABC transporters: Pgp, MRPs 1-6, and BCRP, i.e., ABC transporters that are expressed at the blood-brain barrier (BBB) and, particularly Pgp, are involved in the regulation of brain uptake and extrusion of drugs.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2005

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“…1,2) As a drug efflux transporter, P-gp plays important role in drug absorption, distribution, and excretion. [3][4][5] Inhibition and induction of P-gp function can result in significant drug-drug interactions.The function of P-gp in BBB can significantly limit the brain uptake of its substrate drugs and affect therapeutic outcomes of central nervous system (CNS) acting drugs. By using the ABCB1a/b Ϫ/Ϫ knockout mice, P-gp has been shown to significantly limit the brain entry of a wide variety of structurally unrelated drugs.…”

mentioning

confidence: 99%

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confidence: 99%

Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein

Wang

Zhu

Gibson

et al. 2008

Biological & Pharmaceutical Bulletin

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The drug transporter protein, P-glycoprotein (P-gp), is a member of the ATP-binding cassette (ABC) superfamily that is widely localized at various human tissues including the apical membranes of the gastrointestinal tract, the biliary canalicular membranes of hepatocytes, the luminal membranes of proximal tubular epithelial cells in the kidney, the testes, the placenta and the luminal membranes of endothelial cells of the blood-brain barrier (BBB). 1,2) As a drug efflux transporter, P-gp plays important role in drug absorption, distribution, and excretion. [3][4][5] Inhibition and induction of P-gp function can result in significant drug-drug interactions.The function of P-gp in BBB can significantly limit the brain uptake of its substrate drugs and affect therapeutic outcomes of central nervous system (CNS) acting drugs. By using the ABCB1a/b Ϫ/Ϫ knockout mice, P-gp has been shown to significantly limit the brain entry of a wide variety of structurally unrelated drugs. [6][7][8][9][10][11][12][13][14] Inhibition of P-gp activity can greatly increase P-gp substrate concentrations in brain and may increase their neurotoxicity. [15][16][17] Because of the importance of P-gp in CNS drug disposition, characterization of the binding affinities of CNS drugs for P-gp has clinical implications.Newer antidepressants, i.e. the selective serotonin reuptake inhibitors (SSRIs) and multi-receptor antidepressants, venlafaxine, mirtazapine, bupropion, and nefazodone have advantages over the classical tricyclic antidepressants in lower frequency to cause unwanted side effects and are extensively used worldwide due to established antidepressants efficacy. 18) However, a substantial number of patients with antidepressant therapy still exhibit treatment resistance despite increasing doses. The reason for this resistance is unknown.Recently, the transport efficacy of most of the antidepressants by P-gp has been studied by using the ABCb1a/b Ϫ/Ϫ mouse or in vitro cell culture models [10][11][12]19) except for two drugs, sertraline and bupropion. In these reports, most of the studied antidepressants (e.g. amitriptyline, nortryptyline, citalopram, and trimipramine) were shown to be substrates of P-glycoprotein. [10][11][12]19) These results suggest that the variable expression of P-gp among patients may be an important source of variability in treatment response for the antidepressants.With availability of human P-gp membranes, we have previously used an ATPase assay method to determine the drug stimulated P-gp-ATPase activity and binding affinity of several antipsychotic drugs. 20) Our results indicated that atypical antipsychotic drugs (AAPs), risperidone, and olanzapine, were effectively transported by P-gp. The findings have been verified by our subsequent in vivo Abcb1a/b gene knockout mouse experiments, 13,14) supporting the ATPase assay to provide reliable information of P-gp substrates' binding affinity. In the present report, we studied the binding affinity of sertraline, desmethylsertraline, bupropion and its three major meta...

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“…62 Among OAT family members, rOAT3 has been reported to be localized at the abluminal membrane of brain capillary endothelial cells. 56,63,64 Almost all β-lactam antibiotics, as well as benzylpenicillin and PAH, are substrates of rOAT3 and therefore are likely to be actively transported by OAT3 from brain to plasma across the BBB.…”

Section: -1) Blood-brain and Blood-cerebrospinal Barriersmentioning

confidence: 99%

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

Tsuji¹

2006

Journal of Infection and Chemotherapy

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Drug efflux transporters in the CNS

Cited by 276 publications

References 182 publications

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

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

Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

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