Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis
- 307 Downloads
Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA.
The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship.
A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA.
The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.
KeywordsValproic acid Plasma concentration Pharmacokinetics Single-nucleotide polymorphism UGT2B7 Meta-analysis
This work was supported by grants from the National Science Foundation of China (No. 81460560) and the Applied Basic Research Program of Yunnan Province (No. 2017FB134).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 10.Saito K, Moriya H, Sawaguchi T, Hayakawa T, Nakahara S, Goto A, Arimura Y, Imai K, Kurosawa N, Owada E, Miyamoto A (2006) Haplotype analysis of UDP-glucuronocyltransferase 2B7 gene (UGT2B7) polymorphisms in healthy Japanese subjects. Clin Biochem 39(3):303–308. https://doi.org/10.1016/j.clinbiochem.2006.01.002 CrossRefPubMedGoogle Scholar
- 11.Bhasker CR, McKinnon W, Stone A, Lo ACT, Kubota T, Ishizaki T, Miners JO (2000) Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 10(8):679–685. https://doi.org/10.1097/00008571-200011000-00002 CrossRefPubMedGoogle Scholar
- 13.Wang Q, Zhao L, Liang M, Dong Y, Yun W, Qiu F, Meng H, Guo Y (2016) Effects of UGT2B7 genetic polymorphisms on serum concentrations of valproic acid in Chinese children with epilepsy comedicated with lamotrigine. Ther Drug Monit 38(3):343–349. https://doi.org/10.1097/FTD.0000000000000271 CrossRefPubMedGoogle Scholar
- 15.Sun Y, Yu J, Yuan Q, Wu X, Hu J et al (2017) Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury. Scand J Trauma Resusc Emerg Med 25(1):85. https://doi.org/10.1186/s13049-017-0382-0 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Reny J, Combescure C, Daali Y et al (2012) Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 10(7):1242–1251. https://doi.org/10.1111/j.1538-7836.2012.04756.x CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Chatzistefanidis D, Lazaros L, Giaka K, Nakou I, Tzoufi M, Georgiou I, Kyritsis A, Markoula S (2016) UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels. Pharmacogenomics 17(8):827–835. https://doi.org/10.2217/pgs-2016-0014 CrossRefPubMedGoogle Scholar
- 20.Inoue K, Suzuki E, Yazawa R, Yamamoto Y, Takahashi T, Takahashi Y, Imai K, Koyama S, Inoue Y, Tsuji D, Hayashi H, Itoh K (2014) Influence of uridine diphosphate glucuronosyltransferase 2B7-161C>T polymorphism on the concentration of valproic acid in pediatric epilepsy patients. Ther Drug Monit 36(3):406–409. https://doi.org/10.1097/FTD.0000000000000012 CrossRefPubMedGoogle Scholar
- 21.Ma H, Zhang T, Gong Z, Zhou B, Zou M, Xiao S, Zhu W (2013) Effect of UGT2B7 genetic variants on serum valproic acid concentration. Zhong Nan Da Xue Xue Bao Yi Xue Ban 38(8):766–772. https://doi.org/10.3969/j.issn.1672-7347.2013.08.002 PubMedGoogle Scholar
- 22.Zhang H, Zhang W, Li Y et al (2017) Correlations between UGT2B7∗2 gene polymorphisms and plasma concentrations of carbamazepine and valproic acid in epilepsy patients. Brain Dev S0387-7604(17):30241–30243Google Scholar
- 25.Huo T, Chen X, Lu X, Qu L, Liu Y, Cai S (2014) An effective assessment of valproate sodium-induced hepatotoxicity with UPLC-MS and (1)HNMR-based metabonomics approach. J Chromatogr B Analyt Technol Biomed Life Sci 969:109–116. https://doi.org/10.1016/j.jchromb.2014.08.011 CrossRefPubMedGoogle Scholar
- 27.Holthe M, Rakvåg TN, Klepstad P, Idle JR, Kaasa S, Krokan HE, Skorpen F (2003) Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 3(1):17–26. https://doi.org/10.1038/sj.tpj.6500139 CrossRefPubMedGoogle Scholar
- 29.Innocenti F, Liu W, Fackenthal D, Ramírez J, Chen PX, Ye X, Wu X, Zhang W, Mirkov S, Das S, Cook E Jr, Ratain MJ (2008) Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics 18(8):683–697. https://doi.org/10.1097/FPC.0b013e3283037fe4 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Liu L, Zhao L, Wang Q, Qiu F, Wu X, Ma Y (2015) Influence of valproic acid concentration and polymorphism of UGT1A4*3, UGT2B7-161C > T and UGT2B7*2 on serum concentration of lamotrigine in Chinese epileptic children. Eur J Clin Pharmacol 71(11):1341–1347. https://doi.org/10.1007/s00228-015-1925-9 CrossRefPubMedGoogle Scholar
- 33.Sawyer MB, Innocenti F, Das S, Cheng C, Ramírez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E Jr, Ratain MJ (2003) A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 73(6):566–574. https://doi.org/10.1016/S0009-9236(03)00053-5 CrossRefPubMedGoogle Scholar
- 34.Fattore C, Messina S, Battino D, Croci D, Mamoli D, Perucca E (2006) The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: a case-matched evaluation based on therapeutic drug monitoring data. Epilepsy Res 70(2–3):153–160. https://doi.org/10.1016/j.eplepsyres.2006.04.002 CrossRefPubMedGoogle Scholar
- 35.Perucca E, Grimaldi R, Gatti G, Pirracchio S, Crema F, Frigo GM (1984) Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol 17(6):665–669. https://doi.org/10.1111/j.1365-2125.1984.tb02401.x CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Thibaudeau J, Lépine J, Tojcic J, Duguay Y, Pelletier G, Plante M, Brisson J, Têtu B, Jacob S, Perusse L, Bélanger A, Guillemette C (2006) Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone. Cancer Res 66(1):125–133. https://doi.org/10.1158/0008-5472.CAN-05-2857 CrossRefPubMedGoogle Scholar