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125-73-5Relevant articles and documents
Inhibitory effects of polyphenols and their colonic metabolites on CYP2D6 enzyme using two different substrates
Csepregi, Rita,Fliszár-Nyúl, Eszter,Mladěnka, P?emysl,Mohos, Violetta,Poór, Miklós
, (2020)
Polyphenolic compounds (including flavonoids, chalcones, phenolic acids, and furanocoumarins) represent a common part of our diet, but are also the active ingredients of several dietary supplements and/or medications. These compounds undergo extensive metabolism by human biotransformation enzymes and the microbial flora of the colon. CYP2D6 enzyme metabolizes approximately 25% of the drugs, some of which has narrow therapeutic window. Therefore, its inhibition can lead to the development of pharmacokinetic interactions and the disruption of drug therapy. In this study, the inhibitory effects of 17 plant-derived compounds and 19 colonic flavonoid metabolites on CYP2D6 were examined, employing two assays with different test substrates. The O-demethylation of dextromethorphan was tested employing CypExpress 2D6 kit coupled to HPLC analysis; while the O-demethylation of another CYP2D6 specific substrate (AMMC) was investigated in a plate reader assay with BioVision Fluorometric CYP2D6 kit. Interestingly, some compounds (e.g., bergamottin) inhibited both dextromethorphan and AMMC demethylation; however, certain substances proved to be inhibitors only in one of the assays applied. Our results demonstrate that some polyphenols and colonic metabolites are inhibitors of CYP2D6-catalyzed reactions. Nevertheless, the inhibitory effects showed strong substrate dependence.
Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products
Appiah-Opong, Regina,Commandeur, Jan N.M.,van Vugt-Lussenburg, Barbara,Vermeulen, Nico P.E.
, p. 83 - 91 (2007)
Curcumin (diferuloylmethane) is a major yellow pigment and dietary component derived from Curcuma longa. It has potent anti-inflammatory, anticarcinogenic, antioxidant and chemoprotective activities among others. We studied the interactions of curcumin, a mixture of its decomposition products, and four of its individually identified decomposition products (vanillin, vanillic acid, ferulic aldehyde and ferulic acid) on five major human drug-metabolizing cytochrome P450s (CYPs). Curcumin inhibited CYP1A2 (IC50, 40.0 μM), CYP3A4 (IC50, 16.3 μM), CYP2D6 (IC50, 50.3 μM), CYP2C9 (IC50, 4.3 μM) and CYP2B6 (IC50, 24.5 μM). Curcumin showed a competitive type of inhibition towards CYP1A2, CYP3A4 and CYP2B6, whereas a non-competitive type of inhibition was observed with respect to CYP2D6 and CYP2C9. The inhibitory activity towards CYP3A4, shown by curcumin may have implications for drug-drug interactions in the intestines, in case of high exposure of the intestines to curcumin upon oral administration. In spite of the significant inhibitory activities shown towards the major CYPs in vitro, it remains to be established, whether curcumin will cause significant drug-drug interactions in the liver, given the reported low systemic exposure of the liver to curcumin. The decomposition products of curcumin showed no significant inhibitory activities towards the CYPs investigated, and therefore, are not likely to cause drug-drug interactions at the level of CYPs.
Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites
Ching, Michael S.,Blake, Carolyn L.,Ghabrial, Hany,Ellis, S. Wynne,Lennard, Martin S.,Tucker, Geoffrey T.,Smallwood, Richard A.
, p. 833 - 837 (1995)
The inhibitory effects of dihydroquinidine, quinidine and several quinidine metabolites on cytochrome P450 2D6 (CYP2D6) activity were examined. CYP2D6 heterologously expressed in yeast cells O-demethylated dextromethorphan with a mean K(m) of 5.4 μM and a V(max) of 0.47 nmol/min/nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 metabolic activity (mean K(i) = 0.027 and 0.013 μM, respectively) in yeast microsomes and in human liver microsomes. The metabolites, 3-hydroxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibited CYP2D6, but their K(i) values (0.43 to 2.3 μM) were one to two orders of magnitude weaker than the values for quinidine and dihydroquinidine. There was a trend towards an inverse relationship between K(i) and lipophilicity (r = -0.90, N = 5, P = 0.07), as determined by the retention-time parameter k' using reverse-phase HPLC. Thus, although the metabolites of quinidine have the capacity to inhibit CYP2D6 activity, quinidine and the impurity dihydroquinidine are the important inhibitors of CYP2D6.
Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6
Yamaori, Satoshi,Okamoto, Yasuka,Yamamoto, Ikuo,Watanabe, Kazuhito
, p. 2049 - 2056 (2011)
Δ9-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N- methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC50 =4.01-24.9 μM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent Ki values of 1.16 to 2.69 μM. To clarify the structural requirement for CBD-mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O-demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC50 =7.21 μM) inhibited CYP2D6 activity as potently as CBD did (IC50 =6.52 μM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC50 = 10.2 μM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles. Copyright
Anticonvulsant effects of new morphinan derivatives
Kim, Hyoung-Chun,Nabeshima, Toshitaka,Jhoo, Wang-Kee,Ko, Kwang Ho,Kim, Won-Ki,Shin, Eun-Joo,Cho, Minkyoung,Lee, Phil Ho
, p. 1651 - 1654 (2001)
We synthesized a series of compounds that are modified in positions 3 and 17 of the morphinan ring system, with the intention of developing ideal anticonvulsant agents. We examined the effects of these compounds on kainic acid (KA)-induced seizures, and on locomotor patterns in rats. We found that compounds 5, 6, and 8 exhibit novel anticonvulsant effects, with negligible psychotropic effects.
Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics
Siamoglou, Stavroula,Koromina, Maria,Hishinuma, Eiji,Yamazaki, Shuki,Tsermpini, Evangelia-Eirini,Kordou, Zoe,Fukunaga, Koya,Chantratita, Wasun,Zhou, Yitian,Lauschke, Volker,Mushiroda, Taisei,Hiratsuka, Masahiro,Patrinos, George P.
, (2022/01/20)
Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.
METHODS FOR PREPARING LEVORPHANOL AND RELATED COMPOUNDS, AND COMPOSITIONS THEREOF
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Paragraph 0177-0182, (2020/04/29)
A method for producing substantially pure levorphanol and related compounds, when compared to the conventional process, is provided. In particular, a method for producing substantially pure levorphanol tartrate dihydrate is described. Also described are compositions comprising levorphanol and related compounds, particularly compositions comprising levorphanol tartrate dihydrate, levomethorphan, and norlevorphanol in which the levomethorphan and norlevorphanol are present in the composition in reduced levels.