{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T05:12:39Z","timestamp":1773983559305,"version":"3.50.1"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,6,27]],"date-time":"2011-06-27T00:00:00Z","timestamp":1309132800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2011,7]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold>High plasma levels of fenretinide [N\u2010(4\u2010hydroxyphenyl)retinamide (4\u2010HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4\u2010HPR has been limiting its therapeutic applications. This study characterized metabolism of 4\u2010HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4\u2010HPR plasma levels in mice and to increase the low bioavailability of 4\u2010HPR.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>4\u2010HPR metabolites were identified by mass spectrometric analysis and levels of 4\u2010HPR and its metabolites [N\u2010(4\u2010methoxyphenyl)retinamide (4\u2010MPR) and 4\u2010oxo\u2010N\u2010(4\u2010hydroxyphenyl)retinamide (4\u2010oxo\u20104\u2010HPR)] were quantified by high\u2010performance liquid chromatography (HPLC). Kinetic analysis of enzyme activities and the effects of enzyme inhibitors were performed in pooled human and pooled mouse liver microsomes, and in human cytochrome P450 (CYP) 3A4 isoenzyme microsomes.<jats:italic>In vivo<\/jats:italic>metabolism of 4\u2010HPR was inhibited in mice.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>Six 4\u2010HPR metabolites were identified in the plasma of patients and mice. 4\u2010HPR was oxidized to 4\u2010oxo\u20104\u2010HPR, at least in part via human CYP3A4. The CYP3A4 inhibitor ketoconazole significantly reduced 4\u2010oxo\u20104\u2010HPR formation in both human and mouse liver microsomes. In two strains of mice, co\u2010administration of ketoconazole with 4\u2010HPR<jats:italic>in vivo<\/jats:italic>significantly increased 4\u2010HPR plasma concentrations by &gt; twofold over 4\u2010HPR alone and also increased 4\u2010oxo\u20104\u2010HPR levels.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold>Mice may serve as an<jats:italic>in vivo<\/jats:italic>model of human 4\u2010HPR pharmacokinetics.<jats:italic>In vivo<\/jats:italic>data suggest that the co\u2010administration of ketoconazole at normal clinical doses with 4\u2010HPR may increase systemic exposure to 4\u2010HPR in humans.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2011.01310.x","type":"journal-article","created":{"date-parts":[[2011,3,10]],"date-time":"2011-03-10T14:07:37Z","timestamp":1299766057000},"page":"1263-1275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure"],"prefix":"10.1111","volume":"163","author":[{"given":"Jason P","family":"Cooper","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyunghwa","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hardeep","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C Patrick","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W","family":"Curley Jr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon C","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry J","family":"Maurer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min H","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,6,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.1826"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00320-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20923"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M100343-JLR200"},{"key":"e_1_2_8_6_1","first-page":"6036","article-title":"N\u2010(4\u2010hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid","volume":"53","author":"Delia D","year":"1993","journal-title":"Cancer Res"},{"key":"e_1_2_8_7_1","first-page":"5374","article-title":"Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity","volume":"53","author":"Formelli F","year":"1993","journal-title":"Cancer Res"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-007-0649-7"},{"key":"e_1_2_8_9_1","first-page":"2032","article-title":"Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma","volume":"9","author":"Garaventa A","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2004.22.90140.5056","article-title":"Phase II trial of fenretinide (4\u2010HPR) in recurrent ovarian and primary peritoneal carcinoma: a California cancer consortium trial","volume":"22","author":"Garcia AA","year":"2004","journal-title":"J Clin Oncol"},{"key":"e_1_2_8_11_1","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/S0090-9556(25)09000-2","article-title":"N\u2010(4\u2010hydroxyphenyl)\u2010all\u2010trans\u2010retinamide pharmacokinetics in female rats and mice","volume":"14","author":"Hultin TA","year":"1986","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.01104.x"},{"key":"e_1_2_8_13_1","article-title":"Phase I clinical trial of fenretinide (NSC374551) in advanced solid tumors","author":"Jasti BR","year":"2001","journal-title":"Proc Am Soc Clin Oncol"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920007782798207"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/87.22.1674"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djn076"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1995.13.6.1501"},{"key":"e_1_2_8_18_1","unstructured":"LiuX MaurerB FrgalaT PageJ NokerP FultonRet\u2003al. 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