Blood-brain barrier transport and brain sequestration of propranolol and lidocaine

1984 ◽  
Vol 247 (3) ◽  
pp. R582-R588 ◽  
Author(s):  
W. M. Pardridge ◽  
R. Sakiyama ◽  
G. Fierer
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
High Capacity ◽  
Drug Binding ◽  
Brain Barrier ◽  
Injection Technique ◽  
Blood Brain ◽  
Half Saturation Constant ◽  
Kinetics Of

Lipophilic amine drugs such as propranolol and lidocaine are actively sequestered by tissues via saturable cytoplasmic binding systems. The present studies were designed to characterize the kinetics of drug transport and sequestration in rat brain in vivo by using the carotid injection technique. Both propranolol and lidocaine are sequestered by brain, and the half time (t 1/2) of clearance of the drugs from brain to blood is 6-7 min. The t 1/2 of propranolol association and dissociation reactions with the brain sequestration system are 0.38 +/- 0.03 and 1.33 +/- 0.20 min, respectively. The blood-brain barrier transport of propranolol and lidocaine is inhibited by acid pH, and drug transport is mediated by a low-affinity, high-capacity saturable transport system [propranolol half-saturation constant (Km) = 9.8 +/- 1.2 mM, maximal rate of saturable transport (Vmax) = 5.7 +/- 0.7 mumol X min-1 X g-1, and nonsaturable transport constant (KD) = 0.061 +/- 0.012 ml X min-1 X g-1). These studies indicate that in addition to cerebral blood flow, the distribution of lipophilic amines in brain is a function of plasma pH and of the activity of brain sequestration systems. The latter may represent high-capacity cytoplasmic drug-binding proteins that normally bind endogenous ligands in brain.

scholarly journals Drug transport across the blood–Brain barrier: In Vitro and In Vivo techniques

Drug Delivery ◽  
1998 ◽  
Vol 5 (2) ◽  
pp. 153-153 ◽  
Author(s):  
de Boer A. G ◽  
W. Sutanto ◽  
William M. Pardridge
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Brain Barrier ◽  
Blood Brain

Transfer of nonelectrolytes from blood into peripheral nerve endoneurium

1987 ◽  
Vol 252 (6) ◽  
pp. H1175-H1182 ◽  
Author(s):  
E. Rechthand ◽  
Q. R. Smith ◽  
S. I. Rapoport
Keyword(s):  
Surface Area ◽  
Blood Brain Barrier ◽  
Lipid Membranes ◽  
Brain Barrier ◽  
Solute Flux ◽  
Injection Technique ◽  
Lipid Solubility ◽  
Permeability Coefficients ◽  
Blood Brain

Permeability-surface area (PA) products were determined for the transfer of seven nonelectrolytes across the blood-nerve barrier (BNB) of rat tibial nerve using a quantitative in vivo injection technique. PA values at the BNB for slowly penetrating nonelectrolytes such as urea, mannitol, L-glucose, and sucrose differed by less than threefold from values at the blood-brain barrier in the same animals. Permeability coefficients for transfer across the BNB were calculated assuming both endoneurial capillaries and perineurium contribute to solute flux into endoneurium. Total BNB surface area was determined as 175 cm2/g with morphometric techniques. Calculated permeability coefficients for slowly penetrating nonelectrolytes ranged from 7 X 10(-8) cm/s for sucrose to 4 X 10(-7) cm/s for urea and were directly proportional to solute lipid solubility as measured by the octanol-water partition coefficient. BNB permeability coefficients for sucrose, mannitol, L-glucose, and urea were within 60% of values at cerebral capillaries, of the same order of magnitude as values at aporous lipid membranes, and 100-1,000 times less than values at most nonneural capillaries, such as in skeletal muscle. These results demonstrate that the BNB markedly restricts the transfer of hydrophilic nonelectrolytes between plasma and endoneurium and that diffusion restriction of the BNB is comparable to that of the blood-brain barrier.

scholarly journals Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood–brain barrier

2021 ◽  
Author(s):  
Dominika Luptáková ◽  
Theodosia Vallianatou ◽  
Anna Nilsson ◽  
Reza Shariatgorji ◽  
Margareta Hammarlund-Udenaes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Mass Spectrometry Imaging ◽  
Brain Regions ◽  
Brain Barrier ◽  
Blood Brain ◽  
Comprehensive Determination

AbstractComprehensive determination of the extent of drug transport across the region-specific blood–brain barrier (BBB) is a major challenge in preclinical studies. Multiple approaches are needed to determine the regional free (unbound) drug concentration at which a drug engages with its therapeutic target. We present an approach that merges in vivo and in vitro neuropharmacokinetic investigations with mass spectrometry imaging to quantify and visualize both the extent of unbound drug BBB transport and the post-BBB cerebral distribution of drugs at regional and subregional levels. Direct imaging of the antipsychotic drugs risperidone, clozapine, and olanzapine using this approach enabled differentiation of regional and subregional BBB transport characteristics at 20-µm resolution in small brain regions, which could not be achieved by other means. Our approach allows investigation of heterogeneity in BBB transport and presents new possibilities for molecular psychiatrists by facilitating interpretation of regional target-site exposure results and decision-making.

Drug transport to the brain: comparison between in vitro and in vivo models of the blood-brain barrier

1995 ◽  
Vol 3 (6) ◽  
pp. 357-365 ◽  
Author(s):  
M.P. Dehouck ◽  
B. Dehouck ◽  
C. Schluep ◽  
M. Lemaire ◽  
R. Cecchelli
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Brain Barrier ◽  
In Vivo Models ◽  
Blood Brain ◽  
The Brain

Modulators of Blood-Brain Barrier (BBB) Permeability: In Vitro and in Vivo Drug Transport to the Brain

2001 ◽  
pp. 83-97
Author(s):  
A. G. De Boer ◽  
P. J. Gaillard ◽  
I. C. J. Van Der Sandt ◽  
E. C. M. De Lange ◽  
D. D. Breimer
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Brain

Kinetics of phenylalanine transport at the human blood–brain barrier investigated in vivo

1997 ◽  
Vol 778 (2) ◽  
pp. 329-337 ◽  
Author(s):  
Harald E Möller ◽  
Josef Weglage ◽  
Dirk Wiedermann ◽  
Peter Vermathen ◽  
Ulrich Bick ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Human Blood ◽  
Brain Barrier ◽  
Blood Brain ◽  
Kinetics Of ◽  
Phenylalanine Transport

scholarly journals Enhanced Delivery and Bioactivity of the Neurturin Neurotrophic Factor through Focused Ultrasound—Mediated Blood—Brain Barrier Opening in vivo

2015 ◽  
Vol 35 (4) ◽  
pp. 611-622 ◽  
Author(s):  
Gesthimani Samiotaki ◽  
Camilo Acosta ◽  
Shutao Wang ◽  
Elisa E Konofagou
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurotrophic Factor ◽  
Focused Ultrasound ◽  
Direct Injection ◽  
Brain Barrier ◽  
Injection Technique ◽  
Nigrostriatal Pathway ◽  
Blood Brain

The blood—brain barrier (BBB) constitutes a major obstacle in brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB noninvasively, locally, and transiently to allow large molecules diffusion. Neurturin (NTN), a member of the glial-derived neurotrophic factor (GDNF) family, has been demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. The brain's ascending nigrostriatal pathway is severely damaged in Parkinson's disease (PD), and therefore the substantia nigra (SN) and striatal caudoputamen (CP) were selected as the target areas. The objective of the study was to investigate whether safe and efficient NTN delivery can be achieved through FUS-induced BBB opening via intravenous administration, and thus trigger the neuroregeneration cascade in the nigrostriatal pathway. After the optimization of FUS parameters and target locations in the murine brain, NTN bioavailability and downstream signaling were detected and characterized through immunostaining. FUS significantly enhanced the delivery of NTN compared with the direct injection technique, whereas triggering of the signaling cascade was detected downstream to the neuronal nuclei. These findings thus indicate the potential of the FUS method to mediate transport of proteins through the blood—brain barrier in a PD animal model.

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