Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F16%3A10338223" target="_blank" >RIV/00216208:11160/16:10338223 - isvavai.cz</a>
Result on the web
<a href="http://www.tandfonline.com/doi/full/10.3109/00498254.2015.1076086" target="_blank" >http://www.tandfonline.com/doi/full/10.3109/00498254.2015.1076086</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3109/00498254.2015.1076086" target="_blank" >10.3109/00498254.2015.1076086</a>
Alternative languages
Result language
angličtina
Original language name
Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro
Original language description
The aim of this work was to examine the differences in the inhibitory potency of individual enantiomers and racemic mixtures of selected chiral drugs on human liver microsomal cytochromes P450. The interaction of enantiomeric forms of six drugs (tamsulosin, tolterodine, citalopram, modafinil, zopiclone, ketoconazole) with nine cytochromes P450 (CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1A2) was examined. HPLC methods were used to estimate the extent of the inhibition of specific activity in vitro. Tamsulosin (TAM) and tolterodine (TOL) inhibited CYP3A4 activity with an enantiospecific pattern. The inhibition of CYP3A4 activity differed for R-TAM (K-i 2.88 +/- 0.12 mu M) and S-TAM (K-i 14.22 +/- 0.53 mu M) as well as for S-TOL (K-i 1.71 +/- 0.03 mu M) and R-TOL (K-i 4.78 +/- 0.17 mu M). Also, the inhibition of CYP2C19 by ketoconazole (KET) cis-enantiomers exhibited enantioselective behavior: the (+)-KET (IC50 23.64 +/- 6.25 mu M) was more potent than (-)-KET (IC50 66.12 +/- 12.6 mu M). The inhibition of CYP2C19 by modafinil (MOD) enantiomers (R-MOD IC50 = 51.79 +/- 8.58 mu M, S-MOD IC50 = 48.62 +/- 9.74 mu M) and the inhibition of CYP2D6 by citalopram (CIT) enantiomers (R-CIT IC50 = 68.17 +/- 5.70 mu M, S-CIT IC50 = 62.63 +/- 7.89 mu M) was not enantiospecific. Although enantiospecific interactions were found (TAM, TOL, KET), they are probably not clinically relevant as the plasma levels are generally lower than the drug concentration needed for prominent inhibition (at least 50% of CYP activity).
Czech name
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Czech description
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Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
FR - Pharmacology and apothecary chemistry
OECD FORD branch
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Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Xenobiotica
ISSN
0049-8254
e-ISSN
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Volume of the periodical
46
Issue of the periodical within the volume
4
Country of publishing house
GB - UNITED KINGDOM
Number of pages
10
Pages from-to
315-324
UT code for WoS article
000378173700004
EID of the result in the Scopus database
2-s2.0-84956913409