Kinetics and distribution volumes for tracers of different sizes in the brain plasma space

Smith, Quentin R.; Ziylan, Y. Ziya; Robinson, Peter; Rapoport, Stanley I.

doi:10.1016/0006-8993(88)90577-x

Cited by 49 publications

(33 citation statements)

References 32 publications

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“…The apparent vascular space volume in this study was 11.5 Ϯ 1.4 l/g brain tissue (average Ϯ S.D. ; n ϭ 150 animals), which is in good agreement with the sucrose intravascular volume reported by Smith et al (1988).…”

Section: Methodssupporting

confidence: 91%

Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction

Summerfield

Read²,

Begley³

et al. 2007

J Pharmacol Exp Ther

250

281

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The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (P app ) alongside lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R 2 ϭ 0.82) between P and P app , whereas the uptake of more lipophilic compounds seems to be influenced by both P app and brain free fraction. A nonlinear relationship is observed between logP oct and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.The development of new drugs targeting the central nervous system (CNS) is the fastest growing franchise within the pharmaceutical sector, although this growth has been tempered by relatively poor success of novel candidates (Alavijeh et al., 2005). One of the significant challenges in treating CNS conditions is drug passage across the blood-brain barrier (BBB), a layer of endothelial cells connected with tight junctions that express numerous drug-metabolizing enzymes and efflux transporters (Pardridge, 1997;Tamai and Tsuji, 2000). Therefore, investigation of drug properties that are favorable for CNS delivery can greatly improve efforts in drug discovery.A number of methods are available to determine the rate of uptake of drugs from blood into brain parenchyma (Begley, 1999). In the pharmaceutical industry, CNS penetration is usually assessed in rodents following either intravenous or oral dosing to determine the brain-to-blood concentration ratio. This takes into account not only BBB penetration but also binding, metabolism, and clearance. However, there can be marked species differences in the influence of these parameters on overall BBB penetration; hence, there is significant value in removing some of this complexity and assessing brain penetration at the level of the BBB in situ. Considering that the BBB is conserved across species (Cserr and Bundgaard, 1984), this may represent a more meaningful indicator of the intrinsic ability of the compound to cross the BBB in humans. Furthermore, in situ techniques offer an ideal validation tool for assessing in vitro BBB models, and they also provide further insight into the molecular descriptors that are crucial for BBB penetration.Brain perfusion has been used in neurochemical research for more than 50 years. Early methods focused on long-term perfusion of isolated brain and required extensive surgical Article, publication date, and citation information can be found at

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Section: Methodssupporting

confidence: 91%

Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction

Summerfield

Read²,

Begley³

et al. 2007

J Pharmacol Exp Ther

250

281

View full text Add to dashboard Cite

show abstract

“…The values are presented as mean Ϯ S.D. accomplish this in the current study, the volume of brain vascular space was measured using [ 3 H]inulin, which is assumed to not penetrate the blood-brain barrier (Smith et al, 1988). Our results from total brain homogenates show that the volume of brain vascular space in mice accounts for 1.4% of the whole brain volume (Fig.…”

Section: Directionalmentioning

confidence: 83%

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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“…The observed tissue concentrations were not corrected for plasma volume because 1) it has been shown to be a small proportion of the total tissue (about 6-10%; (Smith et al, 1988)), and 2) the plasma concentration was very small compared to the tissue (10-13%, based on tissue-to-plasma ratios).…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Caudate-putamen dopamine and stereotypy response profiles after intravenous and subcutaneous amphetamine

Cho¹,

Melega²,

Kuczenski

et al. 1999

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We compared the behavioral and caudate-putamen extracellular dopamine responses following intravenous (3.6 mg/kg) and subcutaneous (8 mg/kg) amphetamine administration using 2-min microdialysate sampling intervals, and doses of the drug selected to achieve comparable maximal brain concentrations. Following intravenous amphetamine, dopamine peaked within the first 2 min, then declined with a first-order decay rate of 0.018+/-0.007 min(-1). Following subcutaneous amphetamine, dopamine achieved maximum concentrations at 9 min and remained near peak levels for about 30 min before declining with a first-order decay rate of 0.019+/-0.008 min(-1). Maximal brain amphetamine levels and peak dopamine concentrations were equivalent following either route of drug administration. In contrast to the short latency to maximal extracellular dopamine, the onset of oral stereotypies was delayed until about 30 min following both routes of drug administration. Furthermore, in contrast to the behavioral response to amphetamine, apomorphine administration resulted in the rapid appearance of oral stereotypies within 5-10 min after drug administration. These results suggest that although caudate-putamen dopamine receptor activation may be a critical factor in the expression of focused oral stereotypies, other effects of amphetamine may interfere with the ability of animals to exhibit these behaviors.

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Kinetics and distribution volumes for tracers of different sizes in the brain plasma space

Cited by 49 publications

References 32 publications

Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction

Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction

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

Caudate-putamen dopamine and stereotypy response profiles after intravenous and subcutaneous amphetamine

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