{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T20:44:13Z","timestamp":1770324253257,"version":"3.49.0"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2001,11,8]],"date-time":"2001-11-08T00:00:00Z","timestamp":1005177600000},"content-version":"vor","delay-in-days":252,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2001,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We attempted to predict the <jats:italic>in vivo<\/jats:italic> metabolic clearance of alprazolam from <jats:italic>in vitro<\/jats:italic> metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CL<jats:sub>int<\/jats:sub>) for 4\u2010hydroxylation and CYP3A4 content and between the CL<jats:sub>int<\/jats:sub> for \u03b1\u2010hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CL<jats:sub>int<\/jats:sub> for CYP3A4 was about 2\u2010fold higher than the CL<jats:sub>int<\/jats:sub> for CYP3A5 in the case of 4\u2010hydroxylation. However, the CL<jats:sub>int<\/jats:sub> for CYP3A5 was about 3\u2010fold higher than the CL<jats:sub>int<\/jats:sub> for CYP3A4 in the case of \u03b1\u2010hydroxylation. The metabolic rates for 4\u2010 and \u03b1\u2010hydroxylation increased as the added amount of cytochrome <jats:italic>b<\/jats:italic><jats:sub>5<\/jats:sub> increased, and their maximum values were 3\u2010 to 4\u2010fold higher than those without cytochrome <jats:italic>b<\/jats:italic><jats:sub>5<\/jats:sub>. The values of CL<jats:sub>int<\/jats:sub>, <jats:italic>in vivo<\/jats:italic> predicted from <jats:italic>in vitro<\/jats:italic> studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CL<jats:sub>int<\/jats:sub> value (sum of 4\u2010 and \u03b1\u2010hydroxylation) obtained using three human liver microsomal samples was 4\u2010fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration\u2010time curve (AUC) of alprazolam is reported to increase following co\u2010administration of ketoconazole and the magnitude of the increase predicted from the <jats:italic>in vitro<\/jats:italic> <jats:italic>K<jats:sub>i<\/jats:sub><\/jats:italic> values and reported pharmacokinetic parameters of ketoconazole was 2.30\u20132.45, which is close to the value observed <jats:italic>in vivo<\/jats:italic> (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73\u20131.79 vs 1.58\u20131.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an <jats:italic>in vitro<\/jats:italic>\/<jats:italic>in vivo<\/jats:italic> scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants. Copyright \u00a9 2001 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.261","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T16:22:28Z","timestamp":1030292548000},"page":"53-71","source":"Crossref","is-referenced-by-count":64,"title":["<i>In Vitro<\/i>\/<i>in Vivo<\/i> scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans"],"prefix":"10.1002","volume":"22","author":[{"given":"Noriko","family":"Hirota","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyomi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Iwatsubo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol E.","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles 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