{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T11:31:42Z","timestamp":1772191902992,"version":"3.50.1"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,3,8]],"date-time":"2013-03-08T00:00:00Z","timestamp":1362700800000},"content-version":"vor","delay-in-days":4999,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[1999,7]]},"abstract":"<jats:p><jats:italic>Clinical investigations using isoform\u2010selective probes to phenotype cytochrome P450 activity and interaction studies using isoform\u2010selective inhibitors to determine P450 involvement in drug metabolism assume minimal interday variability in P450 activity. CYP3A4 is the most abundant human P450 isoform and metabolizes approximately half of all therapeutic agents. This investigation evaluated interday variability in hepatic CYP3A4 activity in males, using the clearances of midazolam and alfentanil as metabolic probes. Midazolam (1 mg) followed 1 hour later by alfentanil (20 \u03bcg\/kg) were administered by intravenous bolus to 9 nonsmoking male volunteers (ages 30 8 years). Drug administration was repeated 12 and 20 days later. Venous plasma midazolam and alfentanil concentrations were determined by gas chromatography\/mass spectrometry. Drug clearances were determined by noncompartmental and multiexponential analysis. There were no significant interday differences in plasma drug concentrations or clearances (3.9 1.4, 3.9 1.7, and 4.2 1.7 ml\/kg\/min for alfentanil, respectively, and 6.6 2.0, 7.9 2.4, and 7.9 2.5 ml\/kg\/min for midazolam, respectively, on days 1, 13, and 21 [mean<\/jats:italic> SD<jats:italic>]). Interday variability in clearance was 13% 6% and 19% 12% for alfentanil and midazolam, respectively. Interday variability in the clearance of these probes, and presumably hepatic CYP3A4 activity, was small compared with interindividual variability. Consideration of interday variability in the hepatic metabolism of CYP3A4 substrates does not appear significant in the design of clinical trials<\/jats:italic>.<\/jats:p>","DOI":"10.1177\/00912709922008290","type":"journal-article","created":{"date-parts":[[2003,7,19]],"date-time":"2003-07-19T09:38:13Z","timestamp":1058607493000},"page":"664-669","source":"Crossref","is-referenced-by-count":40,"title":["Intraindividual Variability in Male Hepatic CYP3A4 Activity Assessed by Alfentanil and Midazolam Clearance"],"prefix":"10.1002","volume":"39","author":[{"given":"Evan D.","family":"Kharasch","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole","family":"Jubert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tauri","family":"Senn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. Andrew","family":"Bowdle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth E.","family":"Thummel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,3,8]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02353474"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.3109\/03602539709037591"},{"key":"e_1_2_1_4_2","first-page":"414","article-title":"Inter\u2010individual variations in human liver cytochrome P\u2010450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians","volume":"270","author":"Shimada T","year":"1994","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-2391-5_14"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(95)03155-9"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199550020-00003"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199408000-00001"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(95)00431-9"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199707000-00006"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116607"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199834030-00003"},{"key":"e_1_2_1_13_2","first-page":"549","article-title":"Use of midazolam as a human cytochrome P450 3A probe: I. 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