Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: an open-label, pharmacokinetic interaction clinical trial.
The effects of the CYP3A4 inducer, Hypericum perforatum, on the pharmacokinetics of a single oral dose of ivabradine were assessed. An open-label, 2-period, nonrandomized, phase-I, pharmacokinetic interaction design was used. Twelve healthy volunteers received a single oral dose of ivabradine (10 mg) followed by H perforatum (300 mg orally, 3 times a day) for 14 days, combining the last dose with another single dose of ivabradine. Pharmacokinetic data for ivabradine (S16257) and its main active metabolite (S18982) prior to and after the administration of H perforatum were analyzed. After repeated administration of H perforatum, highest observed concentration in plasma (C(max)) and area under the concentration-time curve (AUC) were significantly decreased for ivabradine (32.7 +/- 16.6 vs 15.4 +/- 7.0 ng/mL, P < .01; 114 +/- 39.1 vs 43.7 +/- 12.0 ng x h/mL, P < .01, respectively), and for S18982 (C(max), 6.8 +/- 3.7 vs 5.1 +/- 2.0 ng/mL, P < .05; AUC, 56.2 +/- 23.4 vs 38.3 +/- 25.1 ng x h/mL, P < .01). Tendencies toward shorter time to C(max) and lower apparent terminal half-life values were found. Pharmacokinetic results are consistent with an induction of ivabradine metabolism by H perforatum.
Portolés
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A
Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, Madrid, Spain. aportoles.hcsc@salud.madrid.org
Terleira
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A
Calvo
A
A
Martínez
I
I
Resplandy
G
G
D000284:Administration, Oral; D000328:Adult; D000873:Anthracenes; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004562:Electrocardiography; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects; D041743:Herb-Drug Interactions; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D020902:Hypericum / Q000737:chemistry*; D000077550:Ivabradine; D008297:Male; D008657:Metabolic Clearance Rate; D010569:Perylene / Q000031:analogs & derivatives / Q000378:metabolism; D028321:Plant Preparations / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets
D000873:Anthracenes; D001552:Benzazepines; D028321:Plant Preparations; C413689:S 18982; D013607:Tablets; D000077550:Ivabradine; C001380:6 beta-hydroxycortisol; D010569:Perylene; C004965:hypericin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone