Influence of Acylpeptide Hydrolase Polymorphisms on Valproic Acid Level in Chinese Epilepsy Patients

Abstract

Background: Concomitant use of meropenem (MEPM) can dramatically decrease valproic acid (VPA) plasma level. It is accepted that inhibition in acylpeptide hydrolase (APEH) activity by MEPM coadministration was the trigger of this drug–drug interaction. Aim: To investigate the influence of APEH genetic polymorphisms on VPA plasma concentration in Chinese epilepsy patients. Patients & methods: Urinary VPA-d6 β-D-glucuronide concentration was determined in 19 patients with VPA treatment alone (n = 10) or concomitant use with MEPM (n = 9). A retrospective study was performed on 149 epilepsy patients to investigate the influence of APEH polymorphisms rs3816877 and rs1131095 on adjusted plasma VPA concentration (C_VPA) at steady-state. Results: Urinary VPA-d6 β-D-glucuronide (VPA-G) concentration was increased significantly in patients with MEPM coadministration. The C_VPA of patients carrying the APEH rs3816877 C/C genotype was significantly higher than that of C/T carriers, and the difference was still obvious when stratified by UGT2B7 rs7668258 polymorphism. Conclusion:APEH polymorphism has significant influence on VPA pharmacokinetics in Chinese population.

Keywords::

• APEH
• genetic polymorphism
• pharmacogenetic
• UGT2B7
• valproic acid

Author contribution

Z-P Wen, J Xiao and X-P Chen participated in research design. Z-P Wen, S-S Fan, C Du, T Yin, B-T Zhou, Z-F Pen, Y Chen and Y-Y Xie conducted experiments. Z-P Wen, W Zhang and X-P Chen performed data analysis. Z-P Wen, J Xiao, J Tang and X-P Chen wrote or contributed to the writing of the manuscript.

Financial & competing interests disclosure

This project was supported by National Nature Science Foundation of China (81373489, 81300204, 81422052 and 81302850), National Science and Technology Major Project (2013ZX09509-107), Hunan Provincial Natural Science Foundation of China (13JJ1010), Funds for Hunan education department program (12K006) and Changsha Major Program of Science Project (K1406004-31, K1308031-11). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This project was supported by National Nature Science Foundation of China (81373489, 81300204, 81422052 and 81302850), National Science and Technology Major Project (2013ZX09509-107), Hunan Provincial Natural Science Foundation of China (13JJ1010), Funds for Hunan education department program (12K006) and Changsha Major Program of Science Project (K1406004-31, K1308031-11). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.