title: Impact of Tetrahydropalmatine on the Pharmacokinetics of Probe Drugs for CYP1A2, 2D6 and 3A Isoenzymes in Beagle Dogs.
abstract: Tetrahydropalmatine (Tet) exhibit multiple pharmacological activities and is used frequently by clinical practitioners. In this study, we evaluate the in vivo effects of single and repeated oral Tet administrations on CYP1A2, 2D6 and 3A activities in six beagle dogs in a randomized, controlled, open-label, crossover study. A cocktail approach, with dosages of the probe drugs caffeine (3.0 mg/kg), metoprolol (2.33 mg/kg) and midazolam (0.45 mg/kg), was used to measure cytochrome P450 (CYP) metabolic activities. The cocktail was administered orally as a single dose (12 mg/kg) 1 day prior to and 4 days after repeated oral Tet administrations (12 mg/kg three times daily). The probe drugs and their metabolites in plasma were quantified simultaneously by a validated HPLC technique, and non-compartmental parameters were used to evaluate metabolic variables for assessment of CYP inhibition or induction. Tet had no or minor impact on the pharmacokinetics and metabolism of the probe drugs caffeine and metoprolol, CYP1A2 and CYP2D6 substrates, respectively. However, Tet increased AUC0-24 h and decreased AUCratio(0-24 h) (1-hydroxymidazolam/midazolam ratio) for midazolam statistically significant, both in single or multiple dosing of Tet, with up to 39 or 57% increase for AUC0-24 h and 29% or 22 decrease for AUCratio(0-24 h), respectively, in line with previous in vitro findings for its CYP3A4 inhibition. The extensive use of Tet and herbal medicines containing Tet makes Tet a candidate for further evaluation of CYP3A-mediated herb-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.|Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Liang
authors.affiliation: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Odd Georg
authors.initials: OG
authors.lastname: Nilsen
mesh_terms: D000818:Animals; D001600:Berberine Alkaloids / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D041743:Herb-Drug Interactions; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry*; D008297:Male
chemical_list: D001600:Berberine Alkaloids; D007527:Isoenzymes; C014215:tetrahydropalmatine; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A
keywords: CYP inhibition; beagle dogs; probe drug cocktail; tetrahydropalmatine