Lack of Correlation between In Vitro and In Vivo Studies on the Inhibitory Effects of (‒)-Sophoranone on CYP2C9 is Attributable to Low Oral Absorption and Extensive Plasma Protein Binding of (‒)-Sophoranone.

Yu Fen Zheng,Soon Uk Chae,Chae Bin Lee,Hyung Joon Shim,Zhouchi Huang,Hunseung Yoo,Doyun Kim,Soo Kyung Bae,Soo Hyeon Bae,Seong Jun Jo

doi:10.3390/pharmaceutics12040328

Yu Fen Zheng, Soon Uk Chae + Show 8 more

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https://doi.org/10.3390/pharmaceutics12040328

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Abstract

(‒)-Sophoranone (SPN) is a bioactive component of Sophora tonkinensis with various pharmacological activities. This study aims to evaluate its in vitro and in vivo inhibitory potential against the nine major CYP enzymes. Of the nine tested CYPs, it exerted the strongest inhibitory effect on CYP2C9-mediated tolbutamide 4-hydroxylation with the lowest IC50 (Ki) value of 0.966 ± 0.149 μM (0.503 ± 0.0383 μM), in a competitive manner. Additionally, it strongly inhibited other CYP2C9-catalyzed diclofenac 4′-hydroxylation and losartan oxidation activities. Upon 30 min pre-incubation of human liver microsomes with SPN in the presence of NADPH, no obvious shift in IC50 was observed, suggesting that SPN is not a time-dependent inactivator of the nine CYPs. However, oral co-administration of SPN had no significant effect on the pharmacokinetics of diclofenac and 4′-hydroxydiclofenac in rats. Overall, SPN is a potent inhibitor of CYP2C9 in vitro but not in vivo. The very low permeability of SPN in Caco-2 cells (Papp value of 0.115 × 10−6 cm/s), which suggests poor absorption in vivo, and its high degree of plasma protein binding (>99.9%) may lead to the lack of in vitro–in vivo correlation. These findings will be helpful for the safe and effective clinical use of SPN.

Highlights

Using human liver microsomes in this study, we evaluated SPN’s potential to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in a reversible and time-dependent manner
We report that SPN is a potent inhibitor of CYP2C9 in vitro but not in vivo
To determine whether the inhibitory effects of SPN on CYP2C9 was substrate specific, we examined the inhibitory effects on other CYP2C9-specific biotransformation pathways and found that SPN markedly inhibited their activities, with IC50 values of 0.879 ± 0.0888 μM and 0.455 ± 0.0486 μM, respectively, (Figure 3)

Summary

Introduction

Of the nine tested CYPs, it exerted the strongest inhibitory effect on CYP2C9-mediated tolbutamide 4-hydroxylation with the lowest IC50 (Ki ) value of 0.966. CYP2C9-catalyzed diclofenac 40 -hydroxylation and losartan oxidation activities. The very low permeability of SPN in Caco-2 cells (Papp value of 0.115 × 10−6 cm/s), which suggests poor absorption in vivo, and its high degree of plasma protein binding (>99.9%) may lead to the lack of in vitro–in vivo correlation. These findings will be helpful for the safe and effective clinical use of SPN

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