Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Kristyna KrasulovaPavel Anzenbacher

Abstract

1. 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. 2. 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. 3. Tamsulosin (TAM) and tolterodine (TOL) inhibited CYP3A4 activity with an enantiospecific pattern. The inhibition of CYP3A4 activity differed for R-TAM (Ki 2.88 ± 0.12 µM) and S-TAM (Ki 14.22 ± 0.53 µM) as well as for S-TOL (Ki 1.71 ± 0.03 µM) and R-TOL (Ki 4.78 ± 0.17 µM). Also, the inhibition of CYP2C19 by ketoconazole (KET) cis-enantiomers exhibited enantioselective behavior: the (+)-KET (IC50 23.64 ± 6.25 µM) was more potent than (-)-KET (IC50 66.12 ± 12.6 µM). The inhibition of CYP2C19 by modafinil (MOD) enantiomers (R-MOD IC50 = 51.79 ± 8.58 µM, S-MOD IC50 = 48.62 ± 9.74 µM) and the inhibition of CYP2D6 by citalopram (CIT) enantiomers (R-CIT IC50 = 68.17 ± 5.70 µM, S-CIT IC50 = 62.63 ± 7.89 µM) ...Continue Reading

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Citations

Mar 25, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alena ŠpičákováLenka Skálová
Jan 10, 2018·Chemistry : a European Journal·Aleksandra A AgeevaTatyana V Leshina
Feb 9, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Constanze KnebelAlbert Braeuning
Jan 13, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Kristyna KrasulovaPavel Anzenbacher
Jan 30, 2019·Pharmaceuticals·Marcin GóreckiGennaro Pescitelli
Nov 4, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kristyna KrasulovaPavel Anzenbacher
Jan 3, 2020·The Journal of Chemical Physics·Nikolay PolyakovTatyana Leshina
Aug 1, 2020·International Journal of Molecular Sciences·Aleksandra A AgeevaTatyana V Leshina
Nov 1, 2020·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Nayara Cristina Perez de AlbuquerqueAnderson Rodrigo Moraes de Oliveira

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