CYP3A5*3 Polymorphism May Influence the Concentration of Valproic Acid

OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2017.495.500 Research Article CYP 3 A 5 * 3 Polymorphism May Influence the Concentration of Valproic Acid Yan Wang and Zhiping Li Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, 201102 Shanghai, China Abstract Background and Objectives: CYP 3 A 5*3 with higher frequency was found to affect the metabolisms of many drugs such as tacrolimus and maraviroc and was proved to be one of the major factors influencing the inter-individual discrepancy in different races. In the present study, the effect of CYP 3 A 5*3 on the plasma concentration and efficacy of valproic acid (VPA) was analyzed to explore the role of CYP 3 A 5*3 in the inter-individual discrepancy. Methodology: A total of 64 children with epilepsy who administered by VPA were recruited. Then, serum VPA concentrations were measured by direct chemiluminescence assay and the polymorphism of CYP 3 A 5 (rs 776746) was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Difference among the CYP 3 A 5 allele on dose, concentration, adjusted concentration (AC), concentration-dose ratio and efficacy of VPA was analyzed by one-way ANOVA or t test. Results: Doses for GG carriers were significantly higher than those for AG carriers (p = 0.037). Moreover, both AC and concentration-dose ratio in patients carrying GG genotype were lower than those in AG type patients (p = 0.049, p = 0.001). However, there was no statistical difference in the frequency of CYP 3 A 5*3 type among controlled, improved and uncontrolled-seizure groups (p = 0.9). Conclusion: The GG genotypes could decrease the AC and concentration-dose ratio of VPA which might provide a potential mechanism underlying inter-individual discrepancy of VPA, however, CYP 3 A 5*3 did not influence the efficacy of VPA Key words: CYP 3 A 5*3, polymorphism, valproic acid, adjusted concentration, concentration-dose ratio, efficacy Received: February 25, 2017 Accepted: May 09, 2017 Published: June 15, 2017 Citation: Yan Wang and Zhiping Li, 2017. CYP 3 A 5*3 polymorphism may influence the concentration of valproic acid. Int. J. Pharmacol., 13: 495-500 Corresponding Author: Zhiping Li, Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, 201102 Shanghai, China Tel: 86+021-64932030 Fax: 86+021-64932030 Copyright: © 2017 Yan Wang and Zhiping Li. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

Int. J. Pharmacol., 13 (5): 495-500, 2017 INTRODUCTION Valproic acid (VPA) was an old antiepileptic drug used for epilepsy for 50 years by virtue of its widely scope effects and kind tolerance 1 . It had been advised by the current National Institute for Health and Care Excellence guidelines as the first line therapy for epilepsy. Due to its wide variation of response, reference range from 50-100 µg mL G 1 was recommended for the VPA monitoring 2 . Increasing studies had determined that age, environment and metabolism discrepancy contribute to the discrepancy of response to VPA The biotransformation of VPA consists of three major metabolic pathways, including uridine diphosphate glucuronosyltransferase (UGT) enzyme pathway, mitochondria $ -oxidation way and cytochrome P 450 (CYP) pathway, accounting for 50, 40 and 10%, respectively 3 . Many researchers had explored that polymorphism of major metabolic enzymes affected the concentration of VPA, however, it was still controversial For the UGT enzyme, Munisamy et al 4 and Feng et al 5 showed that the mutant type of UGT 1 A 4 might lead to an extended half-life, decreased rate of clearance of VPA and caused high concentrations. However, Chatzistefanidis et al 6 and Chu et al 7 found no alternation of concentration between patients carrying mutant type of UGT 1 A 4 (541 A>G, 552 A>C) and wild type. With respect to UGT 2 B 7, studies displayed that the mutant type (C 802 T) of UGT 2 B 7 could decrease the VPA concentration, however, no influence was found in other studies. Disputes also were found in the studies of UGT 2 B 7 161 C>T 8-10 Besides, CYP 2 A 6 , CYP 2 B 6 , CYP 2 C 9 and CYP 2 C 19 were proved to be involved in the metabolic pathway from VPA to 4-ene-VPA 11 . It was showed that the polymorphism of CYP 2 A 6*4 and CYP 2 B 6*6 tended to increase the VPA concentration 12 . However, many researches showed that CYP 2 C 9*2 , CYP 2 C 9*3 and CYP 2 C 19*2 , CYP 2 C 19*3 , CYP 2 C 19*4 , CYP 2 C 19*17 did not affect the VPA concentration 13,14 . Actually, CYP 2 A 6 and CYP 2 B 6 were not the major enzymes in liver or kidney. On the contrary, CYP 3 A 4/3 A 5 in liver metabolized about 70% of drugs. It is found that the polymorphism of CYP 3 A 5 , not CYP 3 A 4 , contributed to the inter-individual variability of drugs 15 . CYP 3 A 5*3 variant, as a single nucleotide polymorphism in intron 3, was the best characterized genetic polymorphism in CYP 3 A 5 16 . More studies have confirmed that CYP 3 A 5*3 are involved in many other diseases, including hypertension and acute leukemia 17,18 . It also plays an important role n the clearance of tacrolimus, sirolimus and lapatinib 19,20 . However, few studies were focused on the VPA plasma concentration. Hence, in this study, the effects of CYP 3 A 5*3 on the plasma concentration and efficacy of VPA were explored MATERIALS AND METHODS Patients: Epilepsy children who were prescribed with VPA for more than three weeks were included in the retrospective study. Patients who had experienced no seizures for more than half a year, or with a decrease of more than 50% of seizures, or continued to experience seizures during VPA monotherapy or polytherapy were classified into controlled-, improved and uncontrolled-seizure group, respectively Determination of VPA concentration: Steady-state concentrations were determined by direct chemiluminescence assay by Viva-E equipment (Siemens), while the linear range was 26.8-150 µg mL G 1 . In order to eliminate error from different weight and dosage, plasma concentration was standardized and expressed as adjusted concentration (AC) = plasma concentration/(daily dose/body weight) [µg kg/(mL g)], or concentration-dose ratio = plasma concentration/daily dose [µg/(mL g)] Genotyping procedures: Residue of plasma was collected after the determination of VPA concentration. Genomic DNA was extracted from blood specimens by TIANamp DNA Blood Mini Kit (TIANGEN, Beijing, China) according to the manufacturerʼs instructions. The CYP 3 A 5*3 polymorphism was determined by a method based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to previously reported procedures 21 Genomic DNA (50 ng) was amplified by TaKaRa Ex Taq (TaKaRa, Dalian, China) containing 0.05 mm Mg 2+ , 25µM dNTP mixture, 1 µM each of forward primer (5ʼ-CTT TAA AGA GCT CTT TTG TCT CTC-3ʼ) and reverse primer (5ʼ-CCA GGA AGC CAG ACT TTG AT-3ʼ) and 1.25 units Ex Taq. Amplification was performed in an i-Cycler thermal cycler (Bio-Rad, Tokyo, Japan). PCR was conducted with an initial denaturation step at 95 for 10 min; amplified for 37 cycles at 94 for 30 sec, 56 for 30 sec, 72 for 30 sec and a final extension step at 72 for 7 min After that, the PCR products were digested for a minimum 2 h at 37 with 5 units of Dde. Then the digested products were electrophoresed on 3% agarose gels. Genotypes were assigned according to fragment sizes (107, 71 and 22 bp product in heterozygote of CYP 3 A 5*3 allele, while 129 and 71 bp in the wild-type). The accuracy of the PCR-RFLP method was confirmed by direct sequencing of the amplified PCR product 496

Int. J. Pharmacol., 13 (5): 495-500, 2017 Statistical analysis: The deviation of genotyping data from the Hardy-Weinberg equilibrium was analyzed by χ 2 test One-way ANOVA (Turkey test) and studentʼs t-test were used to compare quantitative variables, including gender, age, body weight, dose, dosage per weight, concentrations and the distributions of patients taking VPA among AA+AG and GG genotypes 22 . All statistical analysis were performed by Prism 5.0 software. Difference was considered significantly when p<0.05 RESULTS Demographic characteristic: A total of 64 children were recruited and the demographic characteristics are shown in Table 1. The distribution of CYP 3 A 5*3 was consistent with the Hardy-Weinberg equilibrium ( χ 2 = 0.32, p = 0.8) Effects of CYP 3 A 5*3 polymorphism on the concentration, AC and concentration-dose ratio of VPA: There was no statistical difference among AA, AG and GG carriers in age, body weight and plasma concentration. However, the doses prescribed for GG carriers were significantly higher than those AG carriers (p = 0.037). Moreover, both AC and concentration-dose ratio in patients who carrying GG genotype were lower than patients carrying AG genotype (p = 0.049, p = 0.001) (Table 2) Effects of CYP 3 A 5*3 on the AC and concentration-dose ratio in monotherapy and polytherapy: In order to explore whether the effect of CYP 3 A 5*3 was related to the interaction of antiepileptic drugs, patients were divided into monotherapy and polytherapy groups. Results showed that the AC and concentration-dose ratio of GG carriers with monotherapy were slightly decreased, compared with AG carriers, however, there was no statistical discrepancy. Regarding to polytherapy, the mean concentration-dose ratio in children carrying GG was significantly lower than that in children with AG type (p = 0.011) (Table 3) Relationship between the efficacy of VPA and plasma concentration, AC, concentration-dose ratio and CYP 3 A 5*3 polymorphism: Because of the lower AC and concentrationdose ratio in GG carriers, whether the frequency of GG or AG genotype was related to the efficacy of VPA was analyzed further. Results showed that there was no statistical difference neither in the frequency of CYP 3 A 5*3 genotype nor in the Table 1: Demographic data, concentration and polymorphism of CYP 3 A 5 Parameters Values Age (Years) 4.84±0.41 Gender (Male/female) 44 (68.7%)/20 (31.3%) Body weight (kg) 20.03±1.300 VPA dose (g day G 1 ) 0.48±0.035 Plasma VPA concentration (µg mL G 1 ) 75.62±4.490 AC [ : g kg/(mL g)] 3562.00±397.3 Concentration-dose ratio [µg/(mL kg)] 187.60±12.90 Antiepileptic therapy Monotherapy VPA 38 (59.4%) Double medications +LEV 8 (12.5%) +TPM 7 (10.9%) +CZP 2 (3.1%) +OXC 2 (3.1%) +VGB 1 (1.6%) Triple medications +LEV+TPM 3 (4.7%) +LEV+CZP 1 (1.6%) +CZP+LTG 1 (1.6%) +CZP+TPM 1 (1.6%) CYP 3 A 5 polymorphism AA 5 (7.8%) AG 29 (45.3%) GG 30 (46.9%) AC: Adjusted concentration, LEV: Levetiracetam, TPM: Topiramate, CZP: Clonazepam, OXC: Oxcarbazepine, LTG: Lamotrigine, VGB: Vigabatrin. The values were showed as Mean±SEM in age, body weight, VPA dose, plasma VPA concentration, AC and concentration-dose ratio. Values of gender and antiepileptic therapy were expressed with number of patients (%) 497

Int. J. Pharmacol., 13 (5): 495-500, 2017 Table 2: Effects of CYP 3 A 5*3 polymorphism on dose, plasma concentration, AC and concentration-dose ratio of VPA Plasma VPA Concentration Polymorphism No. of Age Gender Body VPA doses concentration AC -dose ratio of CYP 3 A 5 patients (Years) (M/F) weight (kg) (g day G 1 ) (µg mL G 1 ) [µg kg/(mL g)] [µg/(mL g)] AA 5 4.7±1.7 3/2 17.80±3.7 0.50±0.14 87.62±23.37 3085±505.7 189.0±31.8 AG 29 4.4±0.67 22/7 19.40±2.3 0.40±0.039 82.18±7.0 4481±809.8 231.6±21.8 GG 30 5.3±2.9 19/11 20.95±1.6 0.56±0.059 67.27±5.6 2754±247.9 144.8±13.31 AA+AG 34 4.5±0.62 25/9 19.20±2.0 0.42±0.038 82.98±6.7 4275±697.5 225.3±19.20 AG+GG 59 4.85±0.43 41/18 20.21±1.38 0.48±0.037 74.60±4.51 3603±429.0 187.5±13.79 AA vs AG vs GG 0.825 0.76 0.4 0.371 0.394 0.09 AA vs AG 0.878 0.775 0.407 0.778 0.487 0.441 AA vs GG 0.707 0.468 0.699 0.220 0.61 0.217 AG vs GG 0.335 0.591 0.037* 0.098 0.049* 0.001** AA+AG vs GG 0.314 0.508 0.049* 0.076 0.046* 0.001** AA vs AG+GG 0.924 0.623 0.0138* 0.441 0.73 0.975 VPA: Valproic acid, values were showed as Mean±SEM in age, body weight, dose and concentration, *p<0.05 and **p<0.01 Table 3: Effects of CYP 3 A 5*3 on the AC and concentration-dose ratio of monotherapy and polytherapy No.(%) AC [µg kg/(mL g)] Concentration-dose ratio [ : g/(mL kg)] -------------------------------------------- ------------------------------------------------------ ------------------------------------------------- Polymorphism of CYP 3 A 5 Monotherapy Polytherapy Monotherapy Polytherapy Monotherapy Polytherapy AA 4 (6.2) 1 (1.6) 2812±550.4 4173 201.5±37.7 139.1 AG 18 (28.1) 11 (17.2) 3622.5±609.9 5885.1±1867.7 212.3±22.5 263.2±44.1 GG 16 (25) 14 (21.9) 2696.9±353.2 2818.7±358.7 162.5±21.8 124.7±12.7 AA vs. GG 0.881 - 0.41 - AG vs. GG 0.213 0.136 0.124 0.011* VPA: Valproic acid, values of AC and concentration-dose ratio were analyzed with Mean±SEM, *p<0.05 Table 4: Relationship between the efficacy and plasma concentration, AC, concentration-dose ratio and CYP 3 A 5*3 polymorphism Plasma concentration and polymorphism of CYP 3 A 5 Controlled-seizure group Improved-group Uncontrolled-seizure group p-value Plasma VPA concentration (µg mL G 1 ) 76.49±9.2 72.75±7.1 78.37±7.4 0.849 AC [µg kg/(mL g)] 2827±342.2 3329±428.3 4096±852.8 0.883 Concentration-dose ratio [µg/(mL g)] 183.1±14.4 181.9±16.5 195.5±26.2 0.499 AA 3 (4.7%) 1 (1.6%) 1 (1.6%) AG 12 (18.7%) 4 (6.2%) 13 (20.3%) GG 13 (20.3%) 5 (7.8%) 12 (18.7%) 0.888 VPA: Valproic acid, values of plasma VPA concentration, AC and concentration-dose ratio were analyzed with Mean±SEM plasma concentration, AC and concentration-dose ratio among the controlled-improved and uncontrolled-seizure groups. It suggested that CYP 3 A 5*3 might not affect the efficacy of VPA (Table 4) DISCUSSION In this study, it was showed that CYP 3 A 5*3 decreased the AC and concentration-dose ratio of VPA. CYP 3 A 5 was a major enzyme in CYP 3 family and an important deliver of the metabolic clearance of tacrolimus and maraviroc in individuals 23-25 . While, CYP 3 A 5*3 (rs 776746), which showed high frequency and could alter the structure of the enzyme and resulted in less capacity of CYP enzyme, was thought to be involved in the variability of drugs in different races 16 Researches had demonstrated that CYP 3 A 5*3 carrier tended to have higher concentrations of quetiapine and simvastatin in blood 26,27 . However, we found that CYP 3 A 5*3 reduced the adjusted VPA concentrations, which was discordant with the mechanism that the mutant of CYP 3 A 5 should lead to less activity and thus a higher concentration. This might be ascribed to the expression and activity of CYP 3 A 5 in children who carrying CYP 3 A 5*3 and supposing to owe a lower concentration might also be instituted by other abundant enzyme such as CYP 3 A 4 . As is well known, CYP 3 A 4 and CYP 3 A 5 shared about 84% similarity in amino acid sequence Kuang et al 28 especially found that overexpression of CYP 3 A 5 could attenuate induction and activity of CYP 3 A 4 with inducer medication, suggesting that the expression of CYP 3 A 5 could interrupt the content of CYP 3 A 4 and the substantial activity of one isoenzyme might compensate for the reduced activity of another one 29 . In this research, it was interesting 498

Int. J. Pharmacol., 13 (5): 495-500, 2017 that higher dosages were administered to GG carriers, on the contrary, their concentration in plasma were lower than AG carriers, which suggested that the children carrying GG allele might be less nonresponsive to VPA so that the higher doses were prescribed by the physicians The CYP 3 A 5 was proved to affect the response and resistance of many drugs, including the chemoresistance in pancreatic cancer patients, the resistance of imatinib mesylate and the efficacy of amlodipine 30-32 . However, in the present study, we found that there was no significant difference in the frequency of mutant CYP 3 A 5 among controlled-, improvedand uncontrolled-group, which implied that the mutation of CYP 3 A 5 was not directly related to the inefficacy or resistance of VPA, which agreed to some previous studies 33-34 Meanwhile, the efficiency of VPA depended on various factors such as age, progression of epilepsy, age at onset therapy and plasma concentration, which were complicated 35 CONCLUSION The GG genotypes could decrease the AC and concentration-dose ratio of VPA which might provide a potential mechanism underlying inter-individual discrepancy of VPA, however, CYP 3 A 5*3 did not influence the efficacy of VPA SIGNIFICANCE STATEMENTS The present study was planned to explore whether the role of CYP 3 A 5*3 in the inter-individual discrepancy CYP 3 A 5*3 decreased the AC and concentration-dose ratio of VPA which might account for the widely individual discrepancy of VPA CYP 3 A 5*3 could not affect the efficacy of VPA in Chinese epilepsy children ACKNOWLEDGMENT The would like to thank the Important Discipline of Shanghai (No. 20162 B 0305) and National Natural Science Foundation of China (No. 81370776) for supporting this study REFERENCES 1 Rakitin, A., S. Koks and S. Haldre, 2015. Valproate modulates glucose metabolism in patients with epilepsy after first exposure. Epilepsia, 56: e 172-e 175 2 Patsalos, P.N., D.J. Berry, B.F.D. Bourgeois, J.C. Cloyd and T.A. Glauser et al ., 2008. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia, 49: 1239-1276 3 Dickinson, R.G., W.D. Hooper, P.R. Dunstan and M.J. Eadie, 1989. Urinary excretion of valproate and some metabolites in chronically treated patients. Therapeut. Drug Monit., 11: 127-133 4 Munisamy, M., M. Tripathi, M. Behari, S. Raghavan and D.C. Jain et al ., 2013. The effect of uridine diphosphate glucuronosyltransferase (UGT) 1 A 6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: A pharmacogenetic approach. Mol. Diagn. Therapy, 17: 319-326 5 Feng, W., S. Mei, L. Zhu, Y. Yu and W. Yang et al ., 2016. Effects of UGT 1 A 6 and GABRA 1 on standardized valproic acid plasma concentrations and treatment effect in children with epilepsy in China. Therapeut. Drug Monit., 38: 738-743 6 Chatzistefanidis, D., L. Lazaros, K. Giaka, I. Nakou and M. Tzoufi et al ., 2016. UGT 1 A 6-and UGT 2 B 7-related valproic acid Pharmacogenomics according to age groups and total drug concentration levels. Pharmacogenomics, 17: 827-835 7 Chu, X.M., L.F. Zhang, G.J. Wang, S.N. Zhang, J.H. Zhou and H.P. Hao, 2012. Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients. Eur. J. Clin. Pharmacol., 68: 1395-1401 8 Sun, Y.X., W.Y. Zhuo, H. Lin, Z.K. Peng and H.M. Wang et al ., 2015. The influence of UGT 2 B 7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients. Epilepsy Res., 114: 78-80 9 Inoue, K., E. Suzuki, R. Yazawa, Y. Yamamoto and T. Takahashi et al ., 2014. Influence of uridine diphosphate glucuronosyltransferase 2 B 7 161 C>T polymorphism on the concentration of valproic acid in pediatric epilepsy patients. Therapeut. Drug Monit., 36: 406-409 10. Liu, L., L. Zhao, Q. Wang, F. Qiu, X. Wu and Y. Ma, 2015 Influence of valproic acid concentration and polymorphism of UGT 1 A 4*3, UGT 2 B 7-161 C >T and UGT 2 B 7*2 on serum concentration of lamotrigine in Chinese epileptic children. Eur. J. Clin. Pharmacol., 71: 1341-1347 11. Kiang, T.K., P.C. Ho, M.R. Anari, V. Tong, F.S. Abbott and T.K. Chang, 2006. Contribution of CYP 2 C 9, CYP 2 A 6 and CYP 2 B 6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP 2 C 9*1/*1 genotype. Toxicol. Sci., 94: 261-271 12. Tan, L., J.T. Yu, Y.P. Sun, J.R. Ou, J.H. Song and Y. Yu, 2010. The influence of cytochrome oxidase CYP 2 A 6, CYP 2 B 6 and CYP 2 C 9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin. Neurol. Neurosurgery, 112: 320-323 499

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Physician, Epilepsy, Statistical analysis, Pancreatic Cancer, One-way ANOVA, Inter-individual variability, Hypertension, Drug resistance, Single nucleotide polymorphism, Pharmacogenetics, Student's t test, Table 1, Table 2, Table 3, Table 4, Biotransformation, Pancreatic ductal adenocarcinoma, Amlodipine, Childhood absence epilepsy, Urinary Excretion, Plasma concentration, CYP3A4, Polytherapy, Monotherapy, Wild type, AG genotype, GG genotype, Lamotrigine, Chemoresistance, Clonazepam, Imatinib mesylate, Therapeutic drug monitoring, Cytochrome P450, Simvastatin, Genomic DNA, Valproate, Hardy-Weinberg equilibrium, First-Line Therapy, Oxcarbazepine, Maraviroc, PCR-RFLP, PCR product, Seizure control, Reference Range, Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Steady state concentration, Metabolic enzymes, Amino acid sequence, Antiepileptic drug, Valproic acid, Chi-Squared Test, Metabolic pathway, Drug-resistant epilepsy, Agarose gel, National Institute for Health and Care Excellence, CYP3A4 activity, Levetiracetam, Forward primer, Reverse primer, Enzyme polymorphism, CYP2C19, Vigabatrin, Tacrolimus, Acute leukemia, Polymerase chain reaction-restriction fragment length polymorphism, Direct sequencing, Mutant type, CYP3A5 expression, CYP3A5 genotype, CYP3A5 SNPs, National Natural Science Foundation of China, Cytochrome P450 pathway, Genotyping procedures, Demographic characteristic, CYP2B6, Topiramate, Quetiapine, Metabolic clearance, CYP2A6, CYP2C9, Anticonvulsant drug, Adjusted concentration, Lapatinib, Dde, Isoenzyme, GSTT1, Metabolic enzyme, Initial denaturation step.