Quantitative Atlas of Blood–Brain Barrier Transporters, Receptors, and Tight Junction Proteins in Rats and Common Marmoset

Hoshi, Yosuke; Uchida, Yasuo; Tachikawa, Masanori; Inoue, Takashi; Ohtsuki, Sumio; Terasaki, Tetsuya

doi:10.1002/jps.23575

Cited by 208 publications

(276 citation statements)

References 55 publications

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“…Recent proteomic analyses of human and monkey brain microvessels have not revealed any OATP transporters involved in GLB transport at the BBB (15,36). Our in situ brain perfusion experiments in mice have confirmed that GLB brain uptake is not influenced by OATP function.…”

Section: In Situ Brain Perfusion In Micesupporting

confidence: 63%

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

Tournier

Saba

Cisternino

et al. 2013

AAPS J

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Abstract. Glyburide (glibenclamide, GLB) is a widely prescribed antidiabetic with potential beneficial effects in central nervous system injury and diseases. In vitro studies show that GLB is a substrate of organic anion transporting polypeptide (OATP) and ATP-binding cassette (ABC) transporter families, which may influence GLB distribution and pharmacokinetics in vivo. In the present study, we used [11 C] GLB positron emission tomography (PET) imaging to non-invasively observe the distribution of GLB at a non-saturating tracer dose in baboons. The role of OATP and P-glycoprotein (P-gp) in [11 C]GLB whole-body distribution, plasma kinetics, and metabolism was assessed using the OATP inhibitor rifampicin and the dual OATP/P-gp inhibitor cyclosporine. Finally, we used in situ brain perfusion in mice to pinpoint the effect of ABC transporters on GLB transport at the blood-brain barrier (BBB). PET revealed the critical role of OATP on liver [ 11 C]GLB uptake and its subsequent impact on [11 C]GLB metabolism and plasma clearance. OATP-mediated uptake also occurred in the myocardium and kidney parenchyma but not the brain. The inhibition of P-gp in addition to OATP did not further influence [11 C] GLB tissue and plasma kinetics. At the BBB, the inhibition of both P-gp and breast cancer resistance protein (BCRP) was necessary to demonstrate the role of ABC transporters in limiting GLB brain uptake. This study demonstrates that GLB distribution, metabolism, and elimination are greatly dependent on OATP activity, the first step in GLB hepatic clearance. Conversely, P-gp, BCRP, and probably multidrug resistance protein 4 work in synergy to limit GLB brain uptake.

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Section: In Situ Brain Perfusion In Micesupporting

confidence: 63%

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

Tournier

Saba

Cisternino

et al. 2013

AAPS J

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“…This divergence might be related to the P-glycoprotein, a drug efflux transporter located in the blood-brain barrier (BBB). P-glycoprotein was shown to reduce the concentration of PB in the brain, hence leading to loss of efficacy (Loscher and Potschka, 2005) and its expression is 3 folds higher in the rat brain as compared to marmosets and humans (Hoshi et al, 2013). The comparable BBB permeability between humans and marmosets (Hoshi et al, 2013) seems to consist another advantage to accurately forecast the efficacy of AEDs in humans when using these animals for testing.…”

Section: Discussionmentioning

confidence: 99%

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

et al. 2016

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a b s t r a c tThe efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40 mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120 mg/kg) and valproic acid (400 mg/kg) could not prevent PTZinduced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p = 0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p < 0.05), which were also more frequent than in the naïve group (p < 0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY-and FosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

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“…Brain-to-plasma concentration ratios (K p,brain ) of P-gp substrate verapamil and PF-00905556 in monkey are significantly, 10.8-and 12.2-fold, greater than those in mouse and rat, respectively (Hendrikse et al, 1998;Kpakima et al, 2006;Syvanen et al, 2009). Between monkey and rodents, the protein expression levels of P-gp/mdr1a at the BBB differ only by 3-to 4-fold (Kamiie et al, 2008;Ito et al, 2011;Hoshi et al, 2013). Therefore, the remarkable species differences in K p,brain cannot be completely explained by the differences in protein expression levels.…”

Section: Introductionmentioning

confidence: 98%

Blood-Brain Barrier Pharmacoproteomics-Based Reconstruction of the In Vivo Brain Distribution of P-Glycoprotein Substrates in Cynomolgus Monkeys

Uchida

Wakayama

Ohtsuki

et al. 2014

J Pharmacol Exp Ther

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The aim of this study was to investigate whether in vivo drug distribution in brain in monkeys can be reconstructed by integrating four factors: protein expression levels of P-glycoprotein (P-gp)/ multidrug resistance protein 1 at the blood-brain barrier (BBB), in vitro transport activity per P-gp molecule, and unbound drug fractions in plasma and brain. For five P-gp substrates (indinavir, quinidine, loperamide, paclitaxel, and verapamil) and one nonsubstrate (diazepam), in vitro P-gp transport activities were determined by measuring transcellular transport across monolayers of cynomolgus monkey P-gp-transfected LLC-PK1 and parental cells. In vivo P-gp functions at the BBB were reconstructed from in vitro P-gp transport activities and P-gp expression levels in transfected cells and cynomolgus brain microvessels. Brain-to-plasma concentration ratios (K p,brain ) were reconstructed by integrating the reconstructed in vivo P-gp functions with drug unbound fractions in plasma and brain. For all compounds, the reconstructed K p,brain values were within a 3-fold range of observed values, as determined by constant intravenous infusion in adult cynomolgus monkeys. Among four factors, plasma unbound fraction was the most sensitive factor to species differences in K p,brain between monkeys and mice. Unbound brainto-plasma concentration ratios (K p,uu,brain ) were reconstructed as the reciprocal of the reconstructed in vivo P-gp functions, and the reconstructed K p,uu,brain values were within a 3-fold range of in vivo values, which were estimated from observed K p,brain and unbound fractions. This study experimentally demonstrates that brain distributions of P-gp substrates and nonsubstrate can be reconstructed on the basis of pharmacoproteomic concept in monkeys, which serve as a robust model of drug distribution in human brain.

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Quantitative Atlas of Blood–Brain Barrier Transporters, Receptors, and Tight Junction Proteins in Rats and Common Marmoset

Cited by 208 publications

References 55 publications

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

Blood-Brain Barrier Pharmacoproteomics-Based Reconstruction of the In Vivo Brain Distribution of P-Glycoprotein Substrates in Cynomolgus Monkeys

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