TY - JOUR

T1 - A mathematical approach for assessing the transport of large neutral amino acids across the blood-brain barrier in man

AU - Dahl, Rasmus Holmboe

AU - Berg, Ronan M G

PY - 2015

Y1 - 2015

N2 - Changes in the large neutral amino acid (LNAA) transport across the blood-brain barrier (BBB) is thought to contribute to brain dysfunction in a number of clinical conditions, including phenylketonuria, acute liver failure, and sepsis. Here, we present a novel approach for estimating BBB permeability and the LNAA concentrations in brain extracellular fluid, by demonstrating that they can be mathematically derived on the basis of kinetic constants of the BBB available from the literature, if cerebral blood flow and the arterial and jugular venous LNAA concentrations are known. While it is well known that the permeability surface area product of the BBB to a LNAA from blood to brain (PS1) can be calculated from the arterial LNAA concentrations and kinetic constants of the BBB, we demonstrate that the permeability surface area product from brain to blood (PS2) can be calculated by deriving the substrate activity of the saturable transporter from the kinetic constants and arterial and jugular venous LNAA concentrations, and that the concentration of the LNAA in brain extracellular fluid can then be determined. This approach is methodically simple, and may be useful for assessing the transcerebral exchange kinetics of LNAAs in future human-experimental and clinical studies.

AB - Changes in the large neutral amino acid (LNAA) transport across the blood-brain barrier (BBB) is thought to contribute to brain dysfunction in a number of clinical conditions, including phenylketonuria, acute liver failure, and sepsis. Here, we present a novel approach for estimating BBB permeability and the LNAA concentrations in brain extracellular fluid, by demonstrating that they can be mathematically derived on the basis of kinetic constants of the BBB available from the literature, if cerebral blood flow and the arterial and jugular venous LNAA concentrations are known. While it is well known that the permeability surface area product of the BBB to a LNAA from blood to brain (PS1) can be calculated from the arterial LNAA concentrations and kinetic constants of the BBB, we demonstrate that the permeability surface area product from brain to blood (PS2) can be calculated by deriving the substrate activity of the saturable transporter from the kinetic constants and arterial and jugular venous LNAA concentrations, and that the concentration of the LNAA in brain extracellular fluid can then be determined. This approach is methodically simple, and may be useful for assessing the transcerebral exchange kinetics of LNAAs in future human-experimental and clinical studies.

KW - Amino Acids, Neutral/metabolism

KW - Biological Transport

KW - Blood-Brain Barrier/metabolism

KW - Brain/metabolism

KW - Humans

KW - Kinetics

KW - Male

KW - Models, Theoretical

KW - Permeability

M3 - Journal article

C2 - 26994422

VL - 75

SP - 446

EP - 456

JO - Acta Neurobiologiae Experimentalis

JF - Acta Neurobiologiae Experimentalis

SN - 0065-1400

IS - 4

ER -