PMC:6194691 / 177915-182235 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/6194691","sourcedb":"PMC","sourceid":"6194691","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6194691","text":"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.\nTable 6 Overview of efflux routes showing clearance values for substances leaving the brain parenchyma from ISF\nSubstances Features Clearance/µL g−1 min−1\nPassive, non-specific transfer across the blood–brain barrier\n H2Oa, CO2b, O2c, NH3c Very small molecules 1000–7000a, \u003e 6500 largeb\n Methanol, ethanol, antipyrine, isopropanol Highly lipid soluble moleculesd \u003e 100\n Glycerol, ethylene glycol, butyric acid Moderately lipid solubled 100 \u003e CL \u003e 10\nTransfer across the blood–brain barrier by specific transporters\n Glucosee Via GLUT1 50–100\n Lactatef Via MCT1 60–100\n Many substratesg Via Slc22 and Slco transporters 11–364\n Amino acidsh Via L, A, ASC, N, y+, EAAT and others Seeh\n K+i Via several routes including the Na+ pump and NKCC1i 11.3\nEfflux via blood–brain barrier and perivascular fluxes\n Amyloid-βk Primarily across blood–brain barrier ~10k\n Na+ j, Cl− j mannitoll Via both blood–brain barrier and perivascular routes c. 1–2\nEfflux via perivascular routes only\n Sucrose, inulin, albumin, larger dextrans and PEGsm Used as markers for perivascular efflux c. 1\nValues substantially greater than ~ 1 µL g−1 min−1 imply that clearance is primarily across the blood–brain barrier rather than via perivascular efflux\naSee Sect. 5.1\nbSee Sect. 5.2\ncClearance known to be large but difficult to measure\ndSee Fig. 8\neSee Sect. 5.3 and Appendix D\nfSee Sect. 5.4\ngSee Table 1\nhNet 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\niSee Appendix E, NKCC1 is the Na+, K+, 2Cl−—cotransporter; jsee Appendix E\nkSee Sect. 5.7.3\nlSee Appendix B\nmNegligible blood–brain barrier clearance, see Sect. 3 and Appendix B\nTable 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\nPS/(10−2 µL g−1 min−1) keff,BBB/min−1\nMannitol\n Ohno et al. [591] 180 0.0090\n Amtorp [592] 121 0.0061\n Preston et al. [593] 72 0.0036\n Sisson and Oldendorf [594] 10 0.0005\n Daniel et al. [595] 49 0.0025\n Preston and Haas [531] as purchaseda, c 68 0.0034\n Purifiedc 44 0.0022\n Average 0.0040\n s.e.m 0.0013\nSucrose\n Ohno et al. [591] 40 0.002\n Amtorp [592] 20 0.001\n Preston et al. [593] 48 0.0024\n Davson and Spaziani # [596] 22 0.0011\n Reed and Woodbury [597] 5.3 0.00026\n Cameron et al. # [598] 33 0.0017\n Preston and Haas [531] as purchaseda, c 37 0.0019\n Purifiedc 15.3 0.00076\n Smith [599] 24 0.0012\n Preston and Webster 2002 [600] 11.8 0.00059\n Miah et al. [532] radiolabelleda 40 0.002\n Miah et al. [532] mass spec. 4 0.0002\n Average 0.0011\n s.e.m 0.0002\nInulin\n Ohno et al. [591] 1.44–2 0.00008\n Amtorp [592] 15 0.00075\n Preston et al. [593] 9 0.00045\n Reed and Woodbury [597] \u003c ~ 0.3 0.00002\n Daniel et al. [595] 6 0.0003\n Smith [599] \u003c 1.5 0.00006\n Preston and Webster [600] 3.9 0.0002\n Kakee et al. [601]b 30 0.0015\n Average 0.00027\n s.e.m 0.00010\nThe 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. 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