PMC:6194691 / 62018-68411 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-25481827-30706138","span":{"begin":591,"end":593},"obj":"25481827"},{"id":"30340614-21707071-30706139","span":{"begin":595,"end":598},"obj":"21707071"},{"id":"30340614-27503090-30706140","span":{"begin":600,"end":603},"obj":"27503090"},{"id":"30340614-17196184-30706141","span":{"begin":605,"end":608},"obj":"17196184"},{"id":"30340614-12883891-30706142","span":{"begin":610,"end":613},"obj":"12883891"},{"id":"30340614-15717059-30706142","span":{"begin":610,"end":613},"obj":"15717059"},{"id":"30340614-16357150-30706142","span":{"begin":610,"end":613},"obj":"16357150"},{"id":"30340614-22013971-30706142","span":{"begin":610,"end":613},"obj":"22013971"},{"id":"30340614-21854228-30706142","span":{"begin":610,"end":613},"obj":"21854228"},{"id":"30340614-24013810-30706142","span":{"begin":610,"end":613},"obj":"24013810"},{"id":"30340614-23343976-30706142","span":{"begin":610,"end":613},"obj":"23343976"},{"id":"30340614-23506880-30706142","span":{"begin":610,"end":613},"obj":"23506880"},{"id":"30340614-23789957-30706142","span":{"begin":610,"end":613},"obj":"23789957"},{"id":"30340614-27320645-30706142","span":{"begin":610,"end":613},"obj":"27320645"},{"id":"30340614-27783531-30706142","span":{"begin":610,"end":613},"obj":"27783531"},{"id":"30340614-22013971-30706143","span":{"begin":1386,"end":1389},"obj":"22013971"},{"id":"30340614-14579113-30706144","span":{"begin":1569,"end":1572},"obj":"14579113"},{"id":"30340614-9399971-30706145","span":{"begin":2128,"end":2131},"obj":"9399971"},{"id":"30340614-12684544-30706146","span":{"begin":2202,"end":2205},"obj":"12684544"},{"id":"30340614-15504935-30706147","span":{"begin":2274,"end":2277},"obj":"15504935"},{"id":"30340614-16639426-30706148","span":{"begin":2318,"end":2321},"obj":"16639426"},{"id":"30340614-12684544-30706149","span":{"begin":2365,"end":2368},"obj":"12684544"},{"id":"30340614-9694947-30706150","span":{"begin":2419,"end":2422},"obj":"9694947"},{"id":"30340614-9694947-30706151","span":{"begin":2444,"end":2447},"obj":"9694947"},{"id":"30340614-11105986-30706152","span":{"begin":2484,"end":2487},"obj":"11105986"},{"id":"30340614-11105986-30706153","span":{"begin":2516,"end":2519},"obj":"11105986"},{"id":"30340614-11032880-30706154","span":{"begin":2575,"end":2578},"obj":"11032880"},{"id":"30340614-11408557-30706155","span":{"begin":2670,"end":2673},"obj":"11408557"},{"id":"30340614-15292460-30706156","span":{"begin":2730,"end":2733},"obj":"15292460"},{"id":"30340614-15292460-30706157","span":{"begin":2810,"end":2813},"obj":"15292460"},{"id":"30340614-12679720-30706158","span":{"begin":2887,"end":2890},"obj":"12679720"},{"id":"30340614-12358729-30706159","span":{"begin":2940,"end":2943},"obj":"12358729"},{"id":"30340614-23297298-30706160","span":{"begin":2991,"end":2994},"obj":"23297298"},{"id":"30340614-23297298-30706161","span":{"begin":3072,"end":3075},"obj":"23297298"},{"id":"30340614-17365275-30706162","span":{"begin":3136,"end":3139},"obj":"17365275"},{"id":"30340614-9103519-30706163","span":{"begin":3222,"end":3225},"obj":"9103519"},{"id":"30340614-9103519-30706164","span":{"begin":3305,"end":3308},"obj":"9103519"},{"id":"30340614-24136970-30706165","span":{"begin":3448,"end":3451},"obj":"24136970"},{"id":"30340614-11120756-30706166","span":{"begin":3487,"end":3489},"obj":"11120756"},{"id":"30340614-16639426-30706167","span":{"begin":3523,"end":3526},"obj":"16639426"},{"id":"30340614-16639426-30706168","span":{"begin":3630,"end":3633},"obj":"16639426"},{"id":"30340614-16639426-30706169","span":{"begin":3668,"end":3671},"obj":"16639426"},{"id":"30340614-16639426-30706170","span":{"begin":3711,"end":3714},"obj":"16639426"},{"id":"30340614-16639426-30706171","span":{"begin":3753,"end":3756},"obj":"16639426"},{"id":"30340614-16639426-30706172","span":{"begin":4030,"end":4033},"obj":"16639426"},{"id":"30340614-18619525-30706173","span":{"begin":5525,"end":5528},"obj":"18619525"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Efflux mediated in part by SLC solute transporters\nMany of the SLC (solute carrier) transporters (see [202] for a list) are present in the membranes of the endothelial cells of the blood–brain barrier. Some are considered in connection with the transport of specific solutes in Sect. 5. Others, primarily from the SLC21 (OATPs, organic anion transporting polypeptides) and SLC22 (OATs and OCTs, organic anion transporters and organic cation transporters) families are associated with transport of a variety of organic anions and cations. These have been reviewed frequently and extensively [57, 176, 200, 218, 235–246]. (Uppercase labels, e.g. SLC or OAT, strictly refer to human sequences and proteins, while mixed-case labels, e.g. Slc or Oat, refer to any other species. In this review uppercase is also used when there is no intention to specify species).\nThere is little quantitative data on the efflux of organic anions and cations from the parenchyma in humans though many are known to be transported. In rodents more information is available for transfer of organic anions than cations. Table 1 lists some examples of organic anions/neutral molecules for which brain-to-blood transport rate constants have been determined. These are all believed to be substrates for Oat3 (Slc22a8) and/or one or more of the Oatp transporters present at the blood–brain barrier. In broad terms [238], small hydrophobic anions are substrates for Oats (Slc22 family) while larger amphipathic anions are substrates for Oatps (Slc21 family, whose member names start with Slco, see [247]). For comparison Table 1 also lists rate constants and clearances for examples of markers for perivascular efflux. It is clear that the rates of elimination of the Slc substrates are considerably greater than could be supported by perivascular efflux alone.\nTable 1 Comparison of rate constants for efflux and clearances for Slc22 and Slco substrates and the perivascular markers inulin, mannitol and sucrose\nkeff/min−1 t1/2/min Vd/mL/g CL/µL g−1 min−1 Ref # Notes\nSlc substrates Rat unless stated otherwise\n p-Aminohippuric acid (PAH) 0.059 12 0.80 47 [558] Influx much slower than efflux\n p-Aminohippuric acid (PAH) 0.039 18 [559] Abl. Oat3 based on inhibitors, lum. Mrp4 possible based on kidney [560]\n p-Aminohippuric acid (PAH) 0.0175 40 [131]\n Penicillin G, benzylpenicillin 0.043 16 [559] Oat3 based on inhibitors\n Taurocholate 0.023 30 [561]\n BQ-123 0.0078 100 [561]\n Estrone sulfate 0.066 9.9 1.1 75 [562]\n Estrone 0.061 11 3.3 227 [562]\n Dehydroepiandrosterone sulfate (DHEAS) 0.027 26 118 [563] Influx much slower than efflux, Oatp2\n Estradiol-17beta-glucuronide (E217betaG) 0.037 19 [564] Oatp2, 40% and Oat3 20%\n Pravastatin 0.060 12 0.99 59 [565] Oat3 (Slc22a8) and Oatp2 (Slco1a4) + others\n Pitavastatin 0.026 27 14 364 [565] Oat3, Oatp2 (Slco1a4) +others +diffusion\n Homovanillic acid 0.017 40.8 [566] Oat3 from inhibitors\n Indoxyl sulfate 0.011 64 [567] Oat3 and others\n Pemetrexed 0.018 39 0.62 11 [568] Mouse. Oat3 and unknown (not Mrp2 not Bcrp)\n Methotrexate 0.024 29 0.85 20 [568] Oat3 and Bcrp suggested\n Buprenorphine 0.025 27.5 6.1 154 [569] Pgp and unknown, possibly diffusion\n AZT, (3′-azido-3′-deoxythymidine) 0.032 22 [570] Oat3 from benzylpenicillin inhibition\n DDI, (2′,3′-dideoxyinosine) 0.253 2.8 [570] Oat3 from benzylpenicillin inhibition + diffusion\nMarkers for perivascular elimination\n Inulin 0.006 awake0.016 asleep 11543 0.2* 1.23.2 [128] Mouse\n Inulin 0.003 230 0.2* 0.6 [62] Mouse\n Inulin 0.005 135 0.2* 1 [131] Rat\n Mannitol 0.004 170 0.2* 0.8 [25] Mouse\n Sucrose 0.0028 awake0.0043 anesth. 245160 0.2* 0.560.86 [131] Rat\n Albumin 0.006 115 0.2* 1.2 [131] Rat\n Dextran-10K 0.0035 197 0.2* 0.7 [131] Rat\n Dextran-70K 0.004 170 0.2* 0.8 [131] Rat\nkeff rate constant for efflux determined from the time course of the decrease in concentration after injection of solute into the parenchyma (brain efflux index for the Slc substrates relative to inulin; these underestimate keff for values less than ~ 0.01 min−1 see [131]); t1/2 = 0.69/(rate constant) is the half-life; Vd, volume of distribution in the parenchyma determined using brain slices (ISF volume for inulin and mannitol); CL = Vd × keff, the clearance. For the Slc substrates more than one transporter in each membrane is likely to be involved in the transport\n* Assumed equal to ISF volume\nAs indicated in Fig. 10 transport from the parenchyma into the endothelial cells occurs via one or more of the SLC transporters, while exit from the endothelial cells to plasma occurs via either SLC or ABC transporters. For many of the anions efflux from brain to blood is clearly an active uphill process suggesting that the ABC route is dominant (for a caveat see.12) Transport across either membrane can be rate limiting and in many cases transport across each can occur by more than one route. As a consequence demonstration that a specific inhibitor of a transporter reduces the rate of efflux is evidence for involvement of that transporter, but failure to inhibit is relatively uninformative.\nFig. 10 Transport of organic anions across the blood–brain barrier. Organic anion transporters at the blood–brain barrier. The principal known transporters in the rat are shown. In human OAT3 is abluminal, while both OATP1A4 and OATP2B1 are present on both membranes. The ABC efflux pumps, P-gp, BCRP, MRP4 and MRP5, are all localized to the luminal, plasma facing, membrane. The Oat and Oatp transporters are exchangers (see Footnote 12). Localizations from [180] and the references in Table 1\nFor the SLC substrates in Table 1 the half-lives are shorter than the 1–2 h characteristic of markers eliminated from the parenchyma by perivascular efflux (see Sect. 3). As noted earlier, shorter half-lives imply that there are mechanisms for elimination other than perivascular. This is reinforced by noting that the clearances for those solutes for which volumes of distribution are available are much greater than the clearance associated with the perivascular route (see Sect. 3.2). There is ample further evidence (see the references for the entries in Table 1) for the importance of the Oat and Oatp transporters in the elimination of these solutes from the parenchyma including saturation, competition, the availability of transport inhibitors, and the rapid appearance of effluxed material in venous blood draining the head."}

{"project":"2_test","denotations":[{"id":"30340614-25481827-30706138","span":{"begin":591,"end":593},"obj":"25481827"},{"id":"30340614-21707071-30706139","span":{"begin":595,"end":598},"obj":"21707071"},{"id":"30340614-27503090-30706140","span":{"begin":600,"end":603},"obj":"27503090"},{"id":"30340614-17196184-30706141","span":{"begin":605,"end":608},"obj":"17196184"},{"id":"30340614-12883891-30706142","span":{"begin":610,"end":613},"obj":"12883891"},{"id":"30340614-15717059-30706142","span":{"begin":610,"end":613},"obj":"15717059"},{"id":"30340614-16357150-30706142","span":{"begin":610,"end":613},"obj":"16357150"},{"id":"30340614-22013971-30706142","span":{"begin":610,"end":613},"obj":"22013971"},{"id":"30340614-21854228-30706142","span":{"begin":610,"end":613},"obj":"21854228"},{"id":"30340614-24013810-30706142","span":{"begin":610,"end":613},"obj":"24013810"},{"id":"30340614-23343976-30706142","span":{"begin":610,"end":613},"obj":"23343976"},{"id":"30340614-23506880-30706142","span":{"begin":610,"end":613},"obj":"23506880"},{"id":"30340614-23789957-30706142","span":{"begin":610,"end":613},"obj":"23789957"},{"id":"30340614-27320645-30706142","span":{"begin":610,"end":613},"obj":"27320645"},{"id":"30340614-27783531-30706142","span":{"begin":610,"end":613},"obj":"27783531"},{"id":"30340614-22013971-30706143","span":{"begin":1386,"end":1389},"obj":"22013971"},{"id":"30340614-14579113-30706144","span":{"begin":1569,"end":1572},"obj":"14579113"},{"id":"30340614-9399971-30706145","span":{"begin":2128,"end":2131},"obj":"9399971"},{"id":"30340614-12684544-30706146","span":{"begin":2202,"end":2205},"obj":"12684544"},{"id":"30340614-15504935-30706147","span":{"begin":2274,"end":2277},"obj":"15504935"},{"id":"30340614-16639426-30706148","span":{"begin":2318,"end":2321},"obj":"16639426"},{"id":"30340614-12684544-30706149","span":{"begin":2365,"end":2368},"obj":"12684544"},{"id":"30340614-9694947-30706150","span":{"begin":2419,"end":2422},"obj":"9694947"},{"id":"30340614-9694947-30706151","span":{"begin":2444,"end":2447},"obj":"9694947"},{"id":"30340614-11105986-30706152","span":{"begin":2484,"end":2487},"obj":"11105986"},{"id":"30340614-11105986-30706153","span":{"begin":2516,"end":2519},"obj":"11105986"},{"id":"30340614-11032880-30706154","span":{"begin":2575,"end":2578},"obj":"11032880"},{"id":"30340614-11408557-30706155","span":{"begin":2670,"end":2673},"obj":"11408557"},{"id":"30340614-15292460-30706156","span":{"begin":2730,"end":2733},"obj":"15292460"},{"id":"30340614-15292460-30706157","span":{"begin":2810,"end":2813},"obj":"15292460"},{"id":"30340614-12679720-30706158","span":{"begin":2887,"end":2890},"obj":"12679720"},{"id":"30340614-12358729-30706159","span":{"begin":2940,"end":2943},"obj":"12358729"},{"id":"30340614-23297298-30706160","span":{"begin":2991,"end":2994},"obj":"23297298"},{"id":"30340614-23297298-30706161","span":{"begin":3072,"end":3075},"obj":"23297298"},{"id":"30340614-17365275-30706162","span":{"begin":3136,"end":3139},"obj":"17365275"},{"id":"30340614-9103519-30706163","span":{"begin":3222,"end":3225},"obj":"9103519"},{"id":"30340614-9103519-30706164","span":{"begin":3305,"end":3308},"obj":"9103519"},{"id":"30340614-24136970-30706165","span":{"begin":3448,"end":3451},"obj":"24136970"},{"id":"30340614-11120756-30706166","span":{"begin":3487,"end":3489},"obj":"11120756"},{"id":"30340614-16639426-30706167","span":{"begin":3523,"end":3526},"obj":"16639426"},{"id":"30340614-16639426-30706168","span":{"begin":3630,"end":3633},"obj":"16639426"},{"id":"30340614-16639426-30706169","span":{"begin":3668,"end":3671},"obj":"16639426"},{"id":"30340614-16639426-30706170","span":{"begin":3711,"end":3714},"obj":"16639426"},{"id":"30340614-16639426-30706171","span":{"begin":3753,"end":3756},"obj":"16639426"},{"id":"30340614-16639426-30706172","span":{"begin":4030,"end":4033},"obj":"16639426"},{"id":"30340614-18619525-30706173","span":{"begin":5525,"end":5528},"obj":"18619525"}],"text":"Efflux mediated in part by SLC solute transporters\nMany of the SLC (solute carrier) transporters (see [202] for a list) are present in the membranes of the endothelial cells of the blood–brain barrier. Some are considered in connection with the transport of specific solutes in Sect. 5. Others, primarily from the SLC21 (OATPs, organic anion transporting polypeptides) and SLC22 (OATs and OCTs, organic anion transporters and organic cation transporters) families are associated with transport of a variety of organic anions and cations. These have been reviewed frequently and extensively [57, 176, 200, 218, 235–246]. (Uppercase labels, e.g. SLC or OAT, strictly refer to human sequences and proteins, while mixed-case labels, e.g. Slc or Oat, refer to any other species. In this review uppercase is also used when there is no intention to specify species).\nThere is little quantitative data on the efflux of organic anions and cations from the parenchyma in humans though many are known to be transported. In rodents more information is available for transfer of organic anions than cations. Table 1 lists some examples of organic anions/neutral molecules for which brain-to-blood transport rate constants have been determined. These are all believed to be substrates for Oat3 (Slc22a8) and/or one or more of the Oatp transporters present at the blood–brain barrier. In broad terms [238], small hydrophobic anions are substrates for Oats (Slc22 family) while larger amphipathic anions are substrates for Oatps (Slc21 family, whose member names start with Slco, see [247]). For comparison Table 1 also lists rate constants and clearances for examples of markers for perivascular efflux. It is clear that the rates of elimination of the Slc substrates are considerably greater than could be supported by perivascular efflux alone.\nTable 1 Comparison of rate constants for efflux and clearances for Slc22 and Slco substrates and the perivascular markers inulin, mannitol and sucrose\nkeff/min−1 t1/2/min Vd/mL/g CL/µL g−1 min−1 Ref # Notes\nSlc substrates Rat unless stated otherwise\n p-Aminohippuric acid (PAH) 0.059 12 0.80 47 [558] Influx much slower than efflux\n p-Aminohippuric acid (PAH) 0.039 18 [559] Abl. Oat3 based on inhibitors, lum. Mrp4 possible based on kidney [560]\n p-Aminohippuric acid (PAH) 0.0175 40 [131]\n Penicillin G, benzylpenicillin 0.043 16 [559] Oat3 based on inhibitors\n Taurocholate 0.023 30 [561]\n BQ-123 0.0078 100 [561]\n Estrone sulfate 0.066 9.9 1.1 75 [562]\n Estrone 0.061 11 3.3 227 [562]\n Dehydroepiandrosterone sulfate (DHEAS) 0.027 26 118 [563] Influx much slower than efflux, Oatp2\n Estradiol-17beta-glucuronide (E217betaG) 0.037 19 [564] Oatp2, 40% and Oat3 20%\n Pravastatin 0.060 12 0.99 59 [565] Oat3 (Slc22a8) and Oatp2 (Slco1a4) + others\n Pitavastatin 0.026 27 14 364 [565] Oat3, Oatp2 (Slco1a4) +others +diffusion\n Homovanillic acid 0.017 40.8 [566] Oat3 from inhibitors\n Indoxyl sulfate 0.011 64 [567] Oat3 and others\n Pemetrexed 0.018 39 0.62 11 [568] Mouse. Oat3 and unknown (not Mrp2 not Bcrp)\n Methotrexate 0.024 29 0.85 20 [568] Oat3 and Bcrp suggested\n Buprenorphine 0.025 27.5 6.1 154 [569] Pgp and unknown, possibly diffusion\n AZT, (3′-azido-3′-deoxythymidine) 0.032 22 [570] Oat3 from benzylpenicillin inhibition\n DDI, (2′,3′-dideoxyinosine) 0.253 2.8 [570] Oat3 from benzylpenicillin inhibition + diffusion\nMarkers for perivascular elimination\n Inulin 0.006 awake0.016 asleep 11543 0.2* 1.23.2 [128] Mouse\n Inulin 0.003 230 0.2* 0.6 [62] Mouse\n Inulin 0.005 135 0.2* 1 [131] Rat\n Mannitol 0.004 170 0.2* 0.8 [25] Mouse\n Sucrose 0.0028 awake0.0043 anesth. 245160 0.2* 0.560.86 [131] Rat\n Albumin 0.006 115 0.2* 1.2 [131] Rat\n Dextran-10K 0.0035 197 0.2* 0.7 [131] Rat\n Dextran-70K 0.004 170 0.2* 0.8 [131] Rat\nkeff rate constant for efflux determined from the time course of the decrease in concentration after injection of solute into the parenchyma (brain efflux index for the Slc substrates relative to inulin; these underestimate keff for values less than ~ 0.01 min−1 see [131]); t1/2 = 0.69/(rate constant) is the half-life; Vd, volume of distribution in the parenchyma determined using brain slices (ISF volume for inulin and mannitol); CL = Vd × keff, the clearance. For the Slc substrates more than one transporter in each membrane is likely to be involved in the transport\n* Assumed equal to ISF volume\nAs indicated in Fig. 10 transport from the parenchyma into the endothelial cells occurs via one or more of the SLC transporters, while exit from the endothelial cells to plasma occurs via either SLC or ABC transporters. For many of the anions efflux from brain to blood is clearly an active uphill process suggesting that the ABC route is dominant (for a caveat see.12) Transport across either membrane can be rate limiting and in many cases transport across each can occur by more than one route. As a consequence demonstration that a specific inhibitor of a transporter reduces the rate of efflux is evidence for involvement of that transporter, but failure to inhibit is relatively uninformative.\nFig. 10 Transport of organic anions across the blood–brain barrier. Organic anion transporters at the blood–brain barrier. The principal known transporters in the rat are shown. In human OAT3 is abluminal, while both OATP1A4 and OATP2B1 are present on both membranes. The ABC efflux pumps, P-gp, BCRP, MRP4 and MRP5, are all localized to the luminal, plasma facing, membrane. The Oat and Oatp transporters are exchangers (see Footnote 12). Localizations from [180] and the references in Table 1\nFor the SLC substrates in Table 1 the half-lives are shorter than the 1–2 h characteristic of markers eliminated from the parenchyma by perivascular efflux (see Sect. 3). As noted earlier, shorter half-lives imply that there are mechanisms for elimination other than perivascular. This is reinforced by noting that the clearances for those solutes for which volumes of distribution are available are much greater than the clearance associated with the perivascular route (see Sect. 3.2). There is ample further evidence (see the references for the entries in Table 1) for the importance of the Oat and Oatp transporters in the elimination of these solutes from the parenchyma including saturation, competition, the availability of transport inhibitors, and the rapid appearance of effluxed material in venous blood draining the head."}