Drug delivery to tumors of the central nervous system

Lesniak, Maciej S.; Langer, Robert; Brem, Henry

doi:10.1007/s11910-001-0020-z

Cited by 36 publications

(16 citation statements)

References 40 publications

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“…It is conceivable that pemetrexed might also be used for such tumors with the added benefit of less acquired resistance. However, its therapeutic effect will depend largely on the targeted bioavailability of the drug to the CNS site of action, and effective delivery of antitumor compounds across bloodbrain barrier to the brain remains a major challenge in the treatment of brain tumors, including secondary brain tumors (Lesniak et al, 2001). The purpose of this study was to examine the CNS distribution of pemetrexed and to identify the factors that may limit the brain penetration of this compound by using simultaneous arterial blood and brain microdialysis.…”

Section: Discussionmentioning

confidence: 99%

Distribution of the Novel Antifolate Pemetrexed to the Brain

Dai¹,

Chen

Elmquist

2005

J Pharmacol Exp Ther

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Pemetrexed disodium is a novel antifolate that exhibits potent inhibitory effects on multiple enzymes in folate metabolism. Phase II/III clinical trials have shown that pemetrexed is effective against various solid tumors. Like methotrexate, pemetrexed may be useful in treatment of primary and secondary brain tumors. In this study, we examined the central nervous system (CNS) distribution of pemetrexed and the interaction with an organic anion transport inhibitor indomethacin. Male Wistar rats were administered pemetrexed by either single intravenous bolus or constant intravenous infusion. Unbound pemetrexed in blood and brain was measured by simultaneous arterial blood and frontal cortex microdialysis sampling. In the i.v. bolus experiments, indomethacin was administered by i.v. bolus (10 mg/kg) followed by i.v. infusion (0.1 mg/kg/h) in a crossover manner. In the infusion experiments, the same dose of indomethacin was administered after a steady state was reached for pemetrexed. CNS distributional kinetics was analyzed by compartmental and noncompartmental methods. Both bolus and infusion studies showed that pemetrexed has a limited CNS distribution. The mean area under concentrationtime curve (AUC) brain /AUC plasma ratio of unbound pemetrexed was 0.078 Ϯ 0.038 in the i.v. bolus study. The pemetrexed steady-state brain-to-plasma unbound concentration ratio after i.v. infusion was 0.106 Ϯ 0.054. The distributional clearance into the brain was approximately 10% of the clearance out of the brain in both the compartmental and noncompartmental analyses. Indomethacin had no effect on either the brain-toplasma AUC ratio or the steady-state brain-to-plasma concentration ratio. The distribution of pemetrexed into the brain is limited, and an efflux clearance process, such as an efflux transporter, may be involved.

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Section: Discussionmentioning

confidence: 99%

Distribution of the Novel Antifolate Pemetrexed to the Brain

Dai¹,

Chen

Elmquist

2005

J Pharmacol Exp Ther

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“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org A major challenge in the treatment of brain tumors, including secondary brain tumors, is the effective delivery of antitumor compounds across blood-brain barrier into the brain (Lesniak et al, 2001). It is possible that the blood-brain barrier is disrupted by the disease process in brain tumor (Davies, 2002), although the role of the blood-brain barrier in drug delivery to brain tumors has been controversial (Groothuis, 2000).…”

Section: P-glycoprotein Limits Cns Distribution Of Sti-571 1089mentioning

confidence: 99%

Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux

Dai¹,

Marbach²,

Lemaire³

et al. 2002

J Pharmacol Exp Ther

239

180

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The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was determined by examining the directional flux of [14 C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo, using wild-type and mdr1a/b (Ϫ/Ϫ) knockout mice that were orally administered 25 mg/kg [ 14 C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concentration ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (Ϫ/Ϫ) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (Ϫ/Ϫ) mice was approximately 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.

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“…Abraxane, a nanoparticle version of paclitaxel bound to albumin, achieves water solubility without harsh excipients, has been shown to be more effective than previous formulations of paclitaxel, and is the first such chemotherapeutic nanoparticle approved by the FDA [44 ]. In addition to these drug delivery techniques, advances in nanotechnology and polymer sciences have contributed to techniques such as implantable nanoporous membranes [45,46], controlledrelease biochips [47], and transdermal microneedle systems [48].…”

Section: Controlled Drug Deliverymentioning

confidence: 99%