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      Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix Extracts, A Traditional Respiratory Herbal Medicine

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          Abstract

          The extract of Hedera helix L. (Araliaceae), a well-known folk medicine, has been popularly used to treat respiratory problems, worldwide. It is very likely that this herbal extract is taken in combination with conventional drugs. The present study aimed to evaluate the effects of H. helix extract on cytochrome P450 (CYP) enzyme-mediated metabolism to predict the potential for herb–drug interactions. A cocktail probe assay was used to measure the inhibitory effect of CYP. H. helix extracts were incubated with pooled human liver microsomes or CYP isozymes with CYP-specific substrates, and the formation of specific metabolites was investigated to measure the inhibitory effects. H. helix showed significant inhibitory effects on CYP2C8, CYP2C19 and CYP2D6 in a concentration-dependent manner. In recombinant CYP2C8, CYP2C19 and CYP2D6 isozymes, the IC 50 values of the extract were 0.08 ± 0.01, 0.58 ± 0.03 and 6.72 ± 0.22 mg/mL, respectively. Further investigation showed that H. helix extract has a positive time-dependent inhibition property on both CYP2C8 and CYP2C19 with IC 50 shift value of 2.77 ± 0.12 and 6.31 ± 0.25, respectively. Based on this in vitro investigation, consumption of herbal medicines or dietary supplements containing H. helix extracts requires careful attention to avoid any CYP-based interactions.

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          Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions.

          Robert Walsky, R S Obach, Karthik Venkatakrishnan (2007)
          The ability to use vitro inactivation kinetic parameters in scaling to in vivo drug-drug interactions (DDIs) for mechanism-based inactivators of human cytochrome P450 (P450) enzymes was examined using eight human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C(max), estimated hepatic inlet C(max), fraction unbound, in vivo P450 enzyme degradation rate constants estimated from clinical pharmacokinetic data, and fraction of the affected drug cleared by the inhibited enzyme) to predict increases in exposure to drugs, and the predictions were compared with in vivo DDIs gathered from clinical studies reported in the scientific literature. In general, the use of unbound systemic C(max) as the inactivator concentration in vivo yielded the most accurate predictions of DDI with a mean -fold error of 1.64. Abbreviated in vitro approaches to identifying mechanism-based inactivators were developed. Testing potential inactivators at a single concentration (IC(25)) in a 30-min preincubation with human liver microsomes in the absence and presence of NADPH followed by assessment of P450 marker activities readily identified those compounds known to be mechanism-based inactivators and represents an approach that can be used with greater throughput. Measurement of decreases in IC(50) occurring with a 30-min preincubation with liver microsomes and NADPH was also useful in identifying mechanism-based inactivators, and the IC(50) measured after such a preincubation was highly correlated with the k(inact)/K(I) ratio measured after a full characterization of inactivation. Overall, these findings support the conclusion that P450 in vitro inactivation data are valuable in predicting clinical DDIs that can occur via this mechanism.
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            The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America.

            Marion Horn, Yan-Wei Wang, D. Hall … (2009)
            Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.
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              Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks.

              J. Henderson, Hao Sun, Amit S. Kalgutkar … (2012)
              Article 0 comments Cited 31 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 24 July 2017
                Publication date Collection: July 2017
                Volume: 22
                Issue: 7
                Electronic Location Identifier: 1241
                Affiliations
                [1 ]Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan; dr.shaheedmarwat@ 123456yahoo.com
                [2 ]Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea; kis@ 123456hanyang.ac.kr (I.S.K.); chm2456@ 123456hanyang.ac.kr (M.S.C.)
                [3 ]College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon 21983, Korea; kimsh11@ 123456yonsei.ac.kr
                [4 ]School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China; zhangyh@ 123456mails.tjmu.edu.cn
                Author notes
                [* ]Correspondence: yoohh@ 123456hanyang.ac.kr ; Tel.: +82-31-400-5804; Fax: +82-31-400-5958
                Article
                Publisher ID: molecules-22-01241
                DOI: 10.3390/molecules22071241
                PMC ID: 6152208
                PubMed ID: 28737724
                SO-VID: 6ceebb70-57db-4094-820d-63d846cf4851
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 01 June 2017
                Date accepted : 20 July 2017
                Categories
                Subject: Article

                Keywords: hedera helix,araliaceae,cyp inhibition,human liver microsomes,herb–drug interaction
                Data availability:
                Keywords: hedera helix, araliaceae, cyp inhibition, human liver microsomes, herb–drug interaction

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