{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:13:56Z","timestamp":1765545236854},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2004,3,31]],"date-time":"2004-03-31T00:00:00Z","timestamp":1080691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2004,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dexloxiglumide (DEX) is a cholecystokinin type\u20101 receptor antagonist under development for the treatment of constipation\u2010predominant irritable bowel syndrome. Studies of the potential interaction of DEX with human cytochromes P450 (CYPs) were conducted <jats:italic>in vitro<\/jats:italic>. DEX (300\u00b5<jats:sc>M<\/jats:sc>), both with and without a 15\u2010min pre\u2010incubation, was incubated with pooled human liver microsomes and substrates selective for each of eight CYPs. This resulted in &gt;30% inhibition of tolbutamide 4\u2010methyl\u2010hydroxylase (CYP2C9\/10) and lauric acid 11\u2010hydroxylase (CYP2E1) activities. Mean K<jats:sub>i<\/jats:sub> (SD) for CYP2C9\/10 and CYP2E1 were 69.0 (24.3) and 426 (60)\u00b5<jats:sc>M<\/jats:sc>, respectively. Incubations of [<jats:sup>14<\/jats:sup>C]DEX with pooled human liver microsomes produced one major phase I metabolic fraction, with V<jats:sub>max<\/jats:sub>=131 pmol\/min\/mg protein and K<jats:sub>m<\/jats:sub>=23.7\u00b5<jats:sc>M<\/jats:sc>. Further incubations with (i) liver microsomes from 16 individual donors (correlation analysis), (ii) Supersomes\u2122 and (iii) selective chemical inhibitors, implicated CYP3A4\/5, CYP2B6 and CYP2C9 in the formation of this component. Thus, DEX interacts with CYP2C9 both as inhibitor (K<jats:sub>i<\/jats:sub>=69.0\u00b5<jats:sc>M<\/jats:sc>) and as substrate <jats:italic>in vitro<\/jats:italic>. However, based on the maximum concentration (27\u00b5<jats:sc>M<\/jats:sc>) after repeated oral doses of 200mg t.i.d. and the unbound fraction (0.03) of DEX in human plasma, no clinically relevant metabolic interactions with other CYP substrates are predicted. Copyright \u00a9 2004 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.397","type":"journal-article","created":{"date-parts":[[2004,3,31]],"date-time":"2004-03-31T18:01:04Z","timestamp":1080756064000},"page":"163-176","source":"Crossref","is-referenced-by-count":4,"title":["Interaction of dexloxiglumide, a cholecystokinin type\u20101 receptor antagonist, with human cytochromes P450"],"prefix":"10.1002","volume":"25","author":[{"given":"Michael","family":"Hall","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Persiani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen\u2010Ling","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z. 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