title: Time-Dependent Inhibition of CYP2C19 by Isoquinoline Alkaloids: In Vitro and In Silico Analysis.
abstract: The cytochrome P450 2C19 (CYP2C19) enzyme plays an important role in the metabolism of many commonly used drugs. Relatively little is known about CYP2C19 inhibitors, including compounds of natural origin, which could inhibit CYP2C19, potentially causing clinically relevant metabolism-based drug interactions. We evaluated a series (N = 49) of structurally related plant isoquinoline alkaloids for their abilities to interact with CYP2C19 enzyme using in vitro and in silico methods. We examined several common active alkaloids found in herbal products such as apomorphine, berberine, noscapine, and papaverine, as well as the previously identified mechanism-based inactivators bulbocapnine, canadine, and protopine. The IC50 values of the alkaloids ranged from 0.11 to 210 µM, and 42 of the alkaloids were confirmed to be time-dependent inhibitors of CYP2C19. Molecular docking and three-dimensional quantitative structure-activity relationship analysis revealed key interactions of the potent inhibitors with the enzyme active site. We constructed a comparative molecular field analysis model that was able to predict the inhibitory potency of a series of independent test molecules. This study revealed that many of these isoquinoline alkaloids do have the potential to cause clinically relevant drug interactions. These results highlight the need for studying more profoundly the potential interactions between drugs and herbal products. When further refined, in silico methods can be useful in the high-throughput prediction of P450 inhibitory potential of pharmaceutical compounds.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.) kaisa.salminen@uef.fi.
authors.forename: Kaisa A
authors.initials: KA
authors.lastname: Salminen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Minna
authors.initials: M
authors.lastname: Rahnasto-Rilla
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Raija
authors.initials: R
authors.lastname: Väänänen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Peter
authors.initials: P
authors.lastname: Imming
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Achim
authors.initials: A
authors.lastname: Meyer
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Aline
authors.initials: A
authors.lastname: Horling
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (K.A.S., M.R.-R., R.V., A.P., T.L., H.R., M.L.-K.); and Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany (P.I., A.M., A.H.).
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism*; D065689:Cytochrome P-450 CYP2C19 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000470:Alkaloids; D065689:Cytochrome P-450 CYP2C19 Inhibitors; D007546:Isoquinolines; D010936:Plant Extracts; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C039109:isoquinoline