{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:12:36Z","timestamp":1792811556961,"version":"4.5.0"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2003,11,25]],"date-time":"2003-11-25T00:00:00Z","timestamp":1069718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2003,12]]},"abstract":"<jats:p><jats:bold>Summary:\u2002<\/jats:bold>  <jats:italic>Purpose:<\/jats:italic> In clinical studies, topiramate (TPM) was shown to cause a dose\u2010dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription.<\/jats:p><jats:p> <jats:italic>Methods:<\/jats:italic> Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 \u03bc<jats:italic>M<\/jats:italic>) and known inducers, phenobarbital (PB; 2 m<jats:italic>M<\/jats:italic>), and rifampicin (10 \u03bc<jats:italic>M<\/jats:italic>). The rate of testosterone 6\u03b2\u2010hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4\u2010specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cell\u2010based reporter gene assay.<\/jats:p><jats:p> <jats:italic>Results:<\/jats:italic> Compared with controls, TPM (50\u2013500 \u03bc<jats:italic>M<\/jats:italic>)\u2013treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6\u2010 to 8.2\u2010fold), protein levels (4.6\u2010 to 17.3\u2010fold), and mRNA levels (1.9\u2010 to 13.3\u2010fold). Comparatively, rifampicin (10 \u03bc<jats:italic>M<\/jats:italic>) effected 14.5\u2010, 25.3\u2010, and a 20.3\u2010fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50\u2013500 \u03bc<jats:italic>M<\/jats:italic>) caused 1.3\u2010 to 3\u2010fold activation of the hPXR, whereas rifampicin (10 \u03bc<jats:italic>M<\/jats:italic>) caused a 6\u2010fold activation.<\/jats:p><jats:p> <jats:italic>Conclusions:<\/jats:italic> The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high\u2010dose TPM therapy is used.<\/jats:p>","DOI":"10.1111\/j.0013-9580.2003.06203.x","type":"journal-article","created":{"date-parts":[[2003,11,26]],"date-time":"2003-11-26T01:25:32Z","timestamp":1069809932000},"page":"1521-1528","source":"Crossref","is-referenced-by-count":66,"title":["Dose\u2010dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate"],"prefix":"10.1111","volume":"44","author":[{"given":"Srikanth C.","family":"Nallani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy 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