Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro

Popis výsledku v původním jazyce

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).

Název v anglickém jazyce

Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro

Popis výsledku anglicky

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).

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FR - Farmakologie a lékárnická chemie

OECD FORD obor

—

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Xenobiotica

ISSN

0049-8254

e-ISSN

—

Svazek periodika

46

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

315-324

Kód UT WoS článku

000378173700004

EID výsledku v databázi Scopus

2-s2.0-84956913409