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Sökning: id:"swepub:oai:DiVA.org:uu-222386" > Prediction of In Vi...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00003459naa a2200397 4500
001oai:DiVA.org:uu-222386
003SwePub
008140410s2014 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:128378718
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2223862 URI
0247 a https://doi.org/10.1124/dmd.113.0541552 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1283787182 URI
040 a (SwePub)uud (SwePub)ki
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Lundquist, Patriku Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)patlu774
2451 0a Prediction of In Vivo Rat Biliary Drug Clearance from an In Vitro Hepatocyte Efflux Model
264 c 2014-01-06
264 1b American Society for Pharmacology & Experimental Therapeutics (ASPET),c 2014
338 a print2 rdacarrier
520 a Well-established techniques are available to predict in vivo hepatic uptake and metabolism from in vitro data, but predictive models for biliary clearance remain elusive. Several studies have verified the expression and activity of ATP-binding cassette (ABC) efflux transporters central to biliary clearance in freshly isolated rat hepatocytes, raising the possibility of predicting biliary clearance from in vitro efflux measurements. In the present study, short-term plated rat hepatocytes were evaluated as a model to predict biliary clearance from in vitro efflux measurements before major changes in transporter expression known to take place in long-term hepatocyte cultures. The short-term cultures were carefully characterized for their uptake and metabolic properties using a set of model compounds. In vitro efflux was studied using digoxin, fexofenadine, napsagatran, and rosuvastatin, representing compounds with over 100-fold differences in efflux rates in vitro and 60-fold difference in measured in vivo biliary clearance. The predicted biliary clearances from short-term plated rat hepatocytes were within 2-fold of measured in vivo values. As in vitro efflux includes both basolateral and canalicular effluxes, pronounced basolateral efflux may introduce errors in predictions for some compounds. In addition, in vitro rat hepatocyte uptake rates corrected for simultaneous efflux predicted rat in vivo hepatic clearance of the biliary cleared compounds with less than 2-fold error. Short-term plated hepatocytes could thus be used to quantify hepatocyte uptake, metabolism, and efflux of compounds and considerably improve the prediction of hepatic clearance, especially for compounds with a large biliary clearance component.
7001 a Loof, Johan4 aut
7001 a Fagerholm, Urban4 aut
7001 a Sjogren, Ingemo4 aut
7001 a Johansson, Jenny4 aut
7001 a Briem, Sveinn4 aut
7001 a Hoogstraate, Janet4 aut
7001 a Afzelius, Lovisa4 aut
7001 a Andersson, Tommy B.4 aut
7102 a Uppsala universitetb Institutionen för farmaci4 org
7730 t Drug Metabolism And Dispositiond : American Society for Pharmacology & Experimental Therapeutics (ASPET)g 42:3, s. 459-468q 42:3<459-468x 0090-9556x 1521-009X
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-222386
8564 8u https://doi.org/10.1124/dmd.113.054155
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:128378718

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