{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T04:10:08Z","timestamp":1748751008718,"version":"3.41.0"},"reference-count":21,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,12,28]],"date-time":"2015-12-28T00:00:00Z","timestamp":1451260800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The aim of the present study was to further investigate a previously identified metabolic interaction between losartan and paclitaxel, which is one of the marker substrates of CYP2C8, by using human liver microsomes (HLMs) from donors with different CYP2C8 and CYP2C9 genotypes. Although CYP2C8 and CYP2C9 exhibit genetic linkage, previous studies have yet to determine whether losartan or its active metabolite, EXP\u20103174 which is specifically generated by CYP2C9, is responsible for CYP2C8 inhibition. Concentrations of 6\u03b1\u2010hydroxypaclitaxel and EXP\u20103174 were measured by high\u2010performance liquid chromatography after incubations with paclitaxel, losartan or EXP\u20103174 in HLMs from seven donors with different CYP2C8 and CYP2C9 genotypes. The half maximal inhibitory concentration (IC<jats:sub>50<\/jats:sub>) values were not fully dependent on CYP2C8 genotypes. Although the degree of inhibition was small, losartan significantly inhibited the production of 6\u03b1\u2010hydroxypaclitaxel at a concentration of 1 \u03bcmol\/L in only HL20 with the CYP2C8*3\/*3 genotype. HLMs with either CYP2C9*2\/*2 or CYP2C9*1\/*3 exhibited a lower losartan intrinsic clearance (<jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub>\/<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>) than other HLMs including those with CYP2C9*1\/*1 and CYP2C9*1\/*2. Significant inhibition of 6\u03b1\u2010hydroxypaclitaxel formation by EXP\u20103174 could only be found at levels that were 50 times higher (100 \u03bcmol\/L) than the maximum concentration generated in the inhibition study using losartan. These results suggest that the metabolic interaction between losartan and paclitaxel is dependent on losartan itself rather than its metabolite and that the CYP2C8 inhibition by losartan is not affected by the CYP2C9 genotype. Further study is needed to define the effect of CYP2C8 genotypes on losartan\u2013paclitaxel interaction.<\/jats:p>","DOI":"10.1111\/bcpt.12520","type":"journal-article","created":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T14:32:50Z","timestamp":1447079570000},"page":"408-414","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Role of CYP2C8 and CYP2C9 Genotypes in Losartan\u2010Dependent Inhibition of Paclitaxel Metabolism in Human Liver Microsomes"],"prefix":"10.1111","volume":"118","author":[{"given":"Yuji","family":"Mukai","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology Hokkaido Pharmaceutical University School of Pharmacy Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asuna","family":"Senda","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Hokkaido Pharmaceutical University School of Pharmacy Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaki","family":"Toda","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Hokkaido Pharmaceutical University School of Pharmacy Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Eliasson","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska University Hospital Karolinska Institute Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders","family":"Rane","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska University Hospital Karolinska Institute Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuo","family":"Inotsume","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Hokkaido Pharmaceutical University School of Pharmacy Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,12,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.12.267"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2010.487163"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04343.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b14-00366"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12355"},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0090-9556(25)06520-1","article-title":"Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. 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