{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:33:24Z","timestamp":1747146804021,"version":"3.40.5"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,7,16]],"date-time":"2019-07-16T00:00:00Z","timestamp":1563235200000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The study examined the effect of doxorubicin (DOX) on the hepatic expression of CYP2C and its activity for metabolizing tolbutamide (TB), a specific CYP2C substrate, in rats and whether the pharmacokinetics of tolbutamide were altered by doxorubicin exposure. The expression level of hepatic CYP2C11 was depressed 1\u00a0day after doxorubicin administration (day 1), and this effect on CYP2C11 was augmented on day 4. However, the expression level of hepatic CYP2C6 remained unchanged. The activity of tolbutamide 4\u2010hydroxylation in hepatic microsomes was decreased with time following doxorubicin administration. Regarding the enzyme kinetic parameters for tolbutamide 4\u2010hydroxylation on day 4, the maximum velocity (V<jats:sub>max<\/jats:sub>) was significantly lower in the DOX group than that in the control group, while the Michaelis constant (K<jats:sub>m<\/jats:sub>) was unaffected. On pharmacokinetic examination, the total clearance (CL<jats:sub>tot<\/jats:sub>) of tolbutamide on day 4 was increased, despite the decreased metabolic capacity. On the other hand, the serum unbound fraction (f<jats:sub>u<\/jats:sub>) of tolbutamide was elevated with a reduced serum albumin concentration in the DOX group. Contrary to CL<jats:sub>tot<\/jats:sub>, CL<jats:sub>tot<\/jats:sub>\/f<jats:sub>u<\/jats:sub>, a parameter approximated to the hepatic intrinsic clearance of unbound tolbutamide, was estimated to be significantly reduced in the DOX group. These findings indicate that the metabolic capacity of CYP2C11 in the liver is depressed time\u2010dependently by down\u2010regulation after doxorubicin exposure in rats, and that the decreased enzyme activity of TB 4\u2010hydroxylation in hepatic microsomes reflects the pharmacokinetic change of unbound tolbutamide, not total tolbutamide, in serum.<\/jats:p>","DOI":"10.1002\/bdd.2195","type":"journal-article","created":{"date-parts":[[2019,6,19]],"date-time":"2019-06-19T09:34:13Z","timestamp":1560936853000},"page":"225-233","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8125-2589","authenticated-orcid":false,"given":"Shuhei","family":"Fukuno","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy Osaka Ohtani University  3\u201011\u20101 Nishikiori\u2010kita Tondabayashi 584\u20100066 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0753-9861","authenticated-orcid":false,"given":"Katsuhito","family":"Nagai","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy Osaka Ohtani University  3\u201011\u20101 Nishikiori\u2010kita Tondabayashi 584\u20100066 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy Osaka Ohtani University  3\u201011\u20101 Nishikiori\u2010kita Tondabayashi 584\u20100066 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehiro","family":"Tanimura","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy Osaka Ohtani University  3\u201011\u20101 Nishikiori\u2010kita Tondabayashi 584\u20100066 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5225-8375","authenticated-orcid":false,"given":"Takeshi","family":"Nabe","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences Setsunan University  45\u20101 Nagaotouge\u2010cho Hirakata 573\u20100101 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Konishi","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy Osaka Ohtani University  3\u201011\u20101 Nishikiori\u2010kita Tondabayashi 584\u20100066 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,7,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011029226072"},{"key":"e_1_2_7_3_1","first-page":"761","article-title":"Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data","volume":"274","author":"Ashforth E. 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