Functional characterization of five CYP2C8 variants and prediction of CYP2C8 genotype-dependent effects on in vitro and in vivo drug–drug interactions

Abstract

1. To analyze the polymorphic activities of CYP2C8 and evaluate their impact on drug inhibitory potential, three CYP2C8 allelic variants (CYP2C8.2, CYP2C8.3, and CYP2C8.4), two non-synonymous single nucleotide polymorphic variants (R139K and K399R, carried by CYP2C8.3), and wild-type CYP2C8 (CYP2C8.1) were heterologously expressed in yeast, and their enzymatic activities were characterized. CYP2C8 inhibition-based in vitro and in vivo drug–drug interactions (DDIs) in wild-type and variant CYP2C8s were then predicted.

2. Functional characterization of five CYP2C8 variants revealed similar enzymatic activity in R139K and low activity in CYP2C8.2, CYP2C8.3, CYP2C8.4, and K399R compared with CYP2C8.1. The systematic analysis of these CYP2C8 variants can provide more homogeneous data for predicting CYP2C8 phenotypes and could be applied to personalized drug therapy.

3. Prediction of DDIs indicated that CYP2C8.4, R139K, and K399R dramatically alter the IC₅₀ values of nifedipine, troglitazone, and raloxifene, and R139K qualitatively and quantitatively reduces the risk of in vivo paclitaxel–raloxifene and paclitaxel–troglitazone interactions. The results provide the first evidence that CYP2C8 inhibition-based DDIs may be influenced by CYP2C8 genetic polymorphisms. These inhibition data can be used by pharmacologists in the design of in vivo studies to further assess and address the potential role of CYP2C8 genotype-dependent inhibition in clinical DDIs.

Keywords::

• CYP2C8
• genetic polymorphisms
• polymorphic activity
• genotype-dependent drug–drug interactions

Acknowledgement

We thank Professor Yanguang He from Northwest University, Jing Guo, Xin Men from Lifegen Co. (Xi’an, China) for providing guidance and help to the study.

Declaration of interest

The study was supported by grants from the National 863 Program of China (grants nos. 2006AA020705) and “Cheuang Kong Scholars and Innovative Team Development Program” of Ministry of National Education (grants nos. IRT0648). The authors have no conflicts of interest to declare.