Table 6 (see also Tables 1 and 7) lists a number of substances that are cleared by different mechanisms together with indication of the values of their clearances. The last row in the table indicates the clearance of markers for perivascular elimination. These are substances that are known to be neither transported across the blood–brain barrier nor metabolised at a significant rate but leave entirely by perivascular routes (see Appendix B). Each of these markers has a total clearance that is similar to the others. Every water soluble substance in ISF will have a total clearance at least this large, about 1 µL g−1 min−1, because the clearances by other mechanisms will be added on top of this basal value.
Table 6 Overview of efflux routes showing clearance values for substances leaving the brain parenchyma from ISF
Substances Features Clearance/µL g−1 min−1
Passive, non-specific transfer across the blood–brain barrier
 H2Oa, CO2b, O2c, NH3c Very small molecules 1000–7000a, > 6500 largeb
 Methanol, ethanol, antipyrine, isopropanol Highly lipid soluble moleculesd > 100
 Glycerol, ethylene glycol, butyric acid Moderately lipid solubled 100 > CL > 10
Transfer across the blood–brain barrier by specific transporters
 Glucosee Via GLUT1 50–100
 Lactatef Via MCT1 60–100
 Many substratesg Via Slc22 and Slco transporters 11–364
 Amino acidsh Via L, A, ASC, N, y+, EAAT and others Seeh
 K+i Via several routes including the Na+ pump and NKCC1i 11.3
Efflux via blood–brain barrier and perivascular fluxes
 Amyloid-βk Primarily across blood–brain barrier ~10k
 Na+ j, Cl− j mannitoll Via both blood–brain barrier and perivascular routes c. 1–2
Efflux via perivascular routes only
 Sucrose, inulin, albumin, larger dextrans and PEGsm Used as markers for perivascular efflux c. 1
Values substantially greater than ~ 1 µL g−1 min−1 imply that clearance is primarily across the blood–brain barrier rather than via perivascular efflux
aSee Sect. 5.1
bSee Sect. 5.2
cClearance known to be large but difficult to measure
dSee Fig. 8
eSee Sect. 5.3 and Appendix D
fSee Sect. 5.4
gSee Table 1
hNet fluxes at blood–brain barrier 1–20 nmol g−1 min−1, perivascular effluxes (except glutamine) ~ 0.1 nmol g−1 min−1, glutamine ~ 1 nmol g−1 min−1
iSee Appendix E, NKCC1 is the Na+, K+, 2Cl−—cotransporter; jsee Appendix E
kSee Sect. 5.7.3
lSee Appendix B
mNegligible blood–brain barrier clearance, see Sect. 3 and Appendix B
Table 7 Blood–brain permeability-surface area products (PS) from influx data and calculated blood–brain barrier efflux rate constants, keff,BBB for mannitol, sucrose and inulin
PS/(10−2 µL g−1 min−1) keff,BBB/min−1
Mannitol
 Ohno et al. [591] 180 0.0090
 Amtorp [592] 121 0.0061
 Preston et al. [593] 72 0.0036
 Sisson and Oldendorf [594] 10 0.0005
 Daniel et al. [595] 49 0.0025
 Preston and Haas [531] as purchaseda, c  68  0.0034
 Purifiedc 44 0.0022
 Average 0.0040
 s.e.m 0.0013
Sucrose
 Ohno et al. [591] 40 0.002
 Amtorp [592] 20 0.001
 Preston et al. [593] 48 0.0024
 Davson and Spaziani # [596] 22 0.0011
 Reed and Woodbury [597] 5.3 0.00026
 Cameron et al. # [598] 33 0.0017
 Preston and Haas [531] as purchaseda, c  37  0.0019
 Purifiedc 15.3 0.00076
 Smith [599] 24 0.0012
 Preston and Webster 2002 [600] 11.8 0.00059
 Miah et al. [532] radiolabelleda  40  0.002
 Miah et al. [532] mass spec. 4 0.0002
 Average 0.0011
 s.e.m 0.0002
Inulin
 Ohno et al. [591] 1.44–2 0.00008
 Amtorp [592] 15 0.00075
 Preston et al. [593] 9 0.00045
 Reed and Woodbury [597] < ~ 0.3 0.00002
 Daniel et al. [595] 6 0.0003
 Smith [599] < 1.5 0.00006
 Preston and Webster [600] 3.9 0.0002
 Kakee et al. [601]b  30  0.0015
 Average 0.00027
 s.e.m 0.00010
The volume of distribution is assumed to be 0.2 mL g−1. Italic values are excluded from calculations because athey are for comparison with the accompanying values or bit is an outlier, more than 4 st. dev. from the mean of the other values for inulin. The values for mannitol and sucrose marked care reported for the radiolabelled substances both as purchased and following purification to remove impurities which might be transported more rapidly (see text). The average for sucrose is significantly different from than that for mannitol, p = 0.012, and that for inulin different from that for sucrose, p = 0.01. Data obtained with rats (except # in rabbits)