P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

Suzuki, Toyofumi; Zaima, Chika; Moriki, Yoshiaki; Fukami, Toshiro; Tomono, Kazuo

doi:10.1080/10611860601141606

Cited by 33 publications

(29 citation statements)

References 37 publications

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“…In vivo and in vitro studies have demonstrated that various opioids, including morphine, fentanyl and methadone, interact with P-glycoprotein (P-gp), ATP-dependent efflux pump, which is highly expressed on the brain capillaries and play a role to decrease the xenobiotic permeation into the brain (58)(59)(60). Recently, it has shown that P-gp-mediated efflux transport system is involved in buprenorphine transport at the BBB in rats (61), which may contribute to non-linear pharmacokinetics in brain to some extent.…”

Section: Discussionmentioning

confidence: 99%

Buprederm™, a New Transdermal Delivery System of Buprenorphine: Pharmacokinetic, Efficacy and Skin Irritancy Studies

Park¹,

Kim²,

Song³

et al. 2008

Pharm Res

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Section: Discussionmentioning

confidence: 99%

Buprederm™, a New Transdermal Delivery System of Buprenorphine: Pharmacokinetic, Efficacy and Skin Irritancy Studies

Park¹,

Kim²,

Song³

et al. 2008

Pharm Res

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“…Because it isolates efflux processes directly rather than considering efflux as modulator of brain distribution, BEI is an excellent method for determining efflux clearance and studying the mechanisms behind active transport of compounds from the brain. This in vivo method has been extensively used to study the brain efflux clearance of various compounds, including steroid conjugates, valproic acid, nucleoside analogs, buprenorphine, human amyloid-b peptide, and benzylpenicillin and quinidine (Kusuhara et al, 1997;Takasawa et al, 1997;Sugiyama et al, 2001;Kakee et al, 2002;Ohtsuki et al, 2002;Kikuchi et al, 2003;Ito et al, 2006;Suzuki et al, 2007). In our study, we first validated the technique by studying the brain efflux index of valproic acid.…”

Section: Bei Methodsmentioning

confidence: 99%

Brain Efflux Index To Investigate the Influence of Active Efflux on Brain Distribution of Pemetrexed and Methotrexate

Agarwal

Elmquist

2013

Drug Metab Dispos

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Antifolates, in particular methotrexate (MTX), have been widely used in the treatment of primary and secondary tumors of the central nervous system (CNS). Pemetrexed (PMX) is a novel antifolate that also exhibits potent antitumor activity against CNS malignancies. Studies have shown that brain distribution of both antifolates is significantly restricted, possible due to active efflux transport at the blood-brain barrier (BBB). This study characterizes the brain-to-blood transport of PMX and MTX and examines the role of several efflux transporters in brain distribution of the antifolates by use of the intracerebral microinjection technique (brain efflux index). The results from this study show that both PMX and MTX undergo saturable efflux transport across the BBB, with elimination half-lives of approximately 39 minutes and 29 minutes, respectively. Of the various efflux transporters this study investigated, multidrug resistance-associated protein 2 (Mrp2) does not play an important role in the brain distribution of the two antifolate drugs. Interestingly, breast-cancer resistance protein (Bcrp) makes a significant contribution to the brain elimination of MTX but not PMX. In addition, the brain-to-blood transport of both antifolates was inhibited by probenecid and benzylpenicillin, suggesting the involvement of organic anion transporters in the efflux of these compounds from the brain, with organic anion transporter 3 (Oat3) being a possibility. Our results suggest that one of the underlying mechanisms behind the limited brain distribution of PMX and MTX is active efflux transport processes at the BBB, including a benzylpenicillin-sensitive transport system and/or the active transporter Bcrp.

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“…Verapamil is a known Pgp inhibitor widely used to block Pgp function. It was consequently used in cancer combinational therapy [23][24][25]. As shown in figure 4C, verapamil shifted the vinblastine toxicity curve to the left, reaching a calculated GI 50 of 1µM.…”

Section: Cobalamin Decreases Resistance To Vinblastine In Hepg2 Cellsmentioning

confidence: 99%

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Marguerite¹,

Béri-Dexheimer²,

Ortiou³

et al. 2007

Cell Physiol Biochem

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Background: P-glycoprotein (Pgp), produced by multidrug resistance-1 gene (mdr-1), is a main mechanism developed by cancer cells to guard against anti-cancer drugs. Alterations of DNA methylation of the mdr-1 gene promoter are known to be linked to mdr-1 gene expression and are probably related to intracellular S-adenosyl-methionine. We here used HepG2 cells to determine the role of the methionine cycle (through the use of the Methionine-Synthase (MS) cofactor, cobalamin) on mdr-1 gene expression. Methods: Semiquantitative RT-PCR of mdr-1 gene, cellular retention of rhodamine-123, and vinblastine cytotoxicity were carried out on cells cultivated with and without cobalamin. Methylation status of the mdr-1 gene promoter was determined by methylation-specific PCR. Results: Addition of cobalamin to the cells led to an increase in MS activity, to a significant decrease in mdr-1 gene expression which is correlated to an increase in retention of the Pgp substrate Rhodamine 123. Furthermore, cobalamin potentiated cell sensitivity to vinblastine to the same range as that of the Pgp blocker verapamil and prevented methotrexate-induced up-regulation of mdr-1 gene expression. However, no modification in methylation of the mdr-1 gene promoter was observed. Conclusion: Cobalamin downregulates mdr-1 gene expression, as well as Pgp expression and function, and significantly increases cytotoxicity of vinblastine. The identification of this novel way of diminishing cellular resistance to the chemotherapeutic agent vinblastine holds promises of leading to better treatments for cancer patients.

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P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

Cited by 33 publications

References 37 publications

Buprederm™, a New Transdermal Delivery System of Buprenorphine: Pharmacokinetic, Efficacy and Skin Irritancy Studies

Buprederm™, a New Transdermal Delivery System of Buprenorphine: Pharmacokinetic, Efficacy and Skin Irritancy Studies

Brain Efflux Index To Investigate the Influence of Active Efflux on Brain Distribution of Pemetrexed and Methotrexate

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

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