Relevance of CYP2C9 Function in Valproate Therapy

Author(s): Katalin Monostory*, Andrea Nagy, Katalin Tóth, Tamás Bűdi , Ádám Kiss, Máté Déri, Gábor Csukly.

Journal Name: Current Neuropharmacology

Volume 17 , Issue 1 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Background: Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient’s drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways.

Methods: CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions.

Results: The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype.

Conclusion: Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients’ CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children’s anticonvulsant therapy.

Keywords: Valproic acid, epilepsy, psychiatric disorders, CYP2C9 genotype, CYP2C9 expression, personalized medication, pediatric patients.

Shah, R.R.; Smith, R.L. Addressing phenoconversion: the Achilles’ heel of personalized medicine. Br. J. Clin. Pharmacol., 2015, 79(2), 222-240. []. [PMID: 24913012].
Squassina, A.; Manchia, M.; Manolopoulos, V.G.; Artac, M.; Lappa-Manakou, C.; Karkabouna, S.; Mitropoulos, K.; Del Zompo, M.; Patrinos, G.P. Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice. Pharmacogenomics, 2010, 11(8), 1149-1167. []. [PMID: 20712531].
Gervasini, G.; Benítez, J.; Carrillo, J.A. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. Eur. J. Clin. Pharmacol., 2010, 66(8), 755-774. []. [PMID: 20582584].
Shah, R.R.; Shah, D.R. Personalized medicine: is it a pharmacogenetic mirage? Br. J. Clin. Pharmacol., 2012, 74(4), 698-721. []. [PMID: 22591598].
Sim, S.C.; Kacevska, M.; Ingelman-Sundberg, M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J., 2013, 13(1), 1-11. []. [PMID: 23089672].
Lipscomb, J.C.; Poet, T.S. In vitro measurements of metabolism for application in pharmacokinetic modeling. Pharmacol. Ther., 2008, 118(1), 82-103. [ 006]. [PMID: 18374419].
Wilk-Zasadna, I.; Bernasconi, C.; Pelkonen, O.; Coecke, S. Biotransformation in vitro: An essential consideration in the quantitative in vitro-to-in vivo extrapolation (QIVIVE) of toxicity data. Toxicology, 2015, 332, 8-19. [ 2014.10.006]. [PMID: 25456264].
Tóth, K.; Sirok, D.; Kiss, Á.; Mayer, A.; Pátfalusi, M.; Hirka, G.; Monostory, K. Utility of in vitro pharmacokinetic data in prediction of in vivo hepatic clearance of psychopharmacons. Microchem. J., 2018, 136, 193-199. [].
Cederbaum, A.I. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. Redox Biol., 2015, 4, 60-73. [ 2014.11.008]. [PMID: 25498968].
Lewis, D.F. 57 varieties: the human cytochromes P450. Pharmacogenomics, 2004, 5(3), 305-318. [ 5.3.305.29827]. [PMID: 15102545].
Zanger, U.M.; Turpeinen, M.; Klein, K.; Schwab, M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal. Bioanal. Chem., 2008, 392(6), 1093-1108. []. [PMID: 18695978].
Guengerich, F.P. Human Cytochrome P450 Enzymes Cytochrome P450, Structure, Mechanism, and Biochemistry; P.R, F.P., Ed.; Springer: Dordrecht, 2015, pp. 523-785. [ 978-3-319-12108-6_9]
Zhou, S.F.; Liu, J.P.; Chowbay, B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab. Rev., 2009, 41(2), 89-295. []. [PMID: 19514967].
Temesvári, M.; Kóbori, L.; Paulik, J.; Sárváry, E.; Belic, A.; Monostory, K. Estimation of drug-metabolizing capacity by cytochrome P450 genotyping and expression. J. Pharmacol. Exp. Ther., 2012, 341(1), 294-305. []. [PMID: 22262920].
Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther., 2013, 138(1), 103-141. []. [PMID: 23333322].
Samer, C.F.; Lorenzini, K.I.; Rollason, V.; Daali, Y.; Desmeules, J.A. Applications of CYP450 testing in the clinical setting. Mol. Diagn. Ther., 2013, 17(3), 165-184. [ s40291-013-0028-5]. [PMID: 23588782].
Rendic, S.; Guengerich, F.P. Update information on drug metabolism systems--2009, part II: summary of information on the effects of diseases and environmental factors on human cytochrome P450 (CYP) enzymes and transporters. Curr. Drug Metab., 2010, 11(1), 4-84. []. [PMID: 20302566].
Löscher, W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs, 2002, 16(10), 669-694. []. [PMID: 12269861].
Peterson, G.M.; Naunton, M. Valproate: a simple chemical with so much to offer. J. Clin. Pharm. Ther., 2005, 30(5), 417-421. [http://]. [PMID: 16164485].
Chiu, C.T.; Wang, Z.; Hunsberger, J.G.; Chuang, D.M. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol. Rev., 2013, 65(1), 105-142. [http://dx.]. [PMID: 23300133].
Tseng, P.T.; Chen, Y.W.; Chung, W.; Tu, K.Y.; Wang, H.Y.; Wu, C.K.; Lin, P.Y. Significant effect of valproate augmentation therapy in patients with schizophrenia: A meta-analysis study. Medicine (Baltimore), 2016, 95(4), e2475. [ MD.0000000000002475]. [PMID: 26825886].
Sztajnkrycer, M.D. Valproic acid toxicity: overview and management. J. Toxicol. Clin. Toxicol., 2002, 40(6), 789-801. [http://dx.]. [PMID: 12475192].
Perucca, E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs, 2002, 16(10), 695-714. []. [PMID: 12269862].
Chateauvieux, S.; Morceau, F.; Dicato, M.; Diederich, M. Molecular and therapeutic potential and toxicity of valproic acid. J. Biomed. Biotechnol., 2010, 2010, 479364. [ 2010/479364]. [PMID: 20798865].
Nanau, R.M.; Neuman, M.G. Adverse drug reactions induced by valproic acid. Clin. Biochem., 2013, 46(15), 1323-1338. [http://dx.]. [PMID: 23792104].
König, S.A.; Siemes, H.; Bläker, F.; Boenigk, E.; Gross-Selbeck, G.; Hanefeld, F.; Haas, N.; Köhler, B.; Koelfen, W.; Korinthenberg, R.; Kurek, E.; Lenard, H-G.; Penin, H.; Penzien, J.M.; Schünke, W.; Schultze, C.; Stephani, U.; Stute, M.; Traus, M.; Weinmann, H-M.; Scheffner, W. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia, 1994, 35(5), 1005-1015. []. [PMID: 7925143].
Guerrini, R. Valproate as a mainstay of therapy for pediatric epilepsy. Paediatr. Drugs, 2006, 8(2), 113-129. [ 2165/00148581-200608020-00004]. [PMID: 16608372].
Kochen, W.; Schneider, A.; Ritz, A. Abnormal metabolism of valproic acid in fatal hepatic failure. Eur. J. Pediatr., 1983, 141(1), 30-35. []. [PMID: 6416845].
Fisher, E.; Siemes, H.; Pund, R.; Wittfoht, W.; Nau, H. Valproate metabolites in serum and urine during antiepileptic therapy in children with infantile spasms: abnormal metabolite pattern associated with reversible hepatotoxicity. Epilepsia, 1992, 33(1), 165-171. []. [PMID: 1733752].
Siemes, H.; Nau, H.; Schultze, K.; Wittfoht, W.; Drews, E.; Penzien, J.; Seidel, U. Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity. Epilepsia, 1993, 34(2), 332-346. [ tb02419.x]. [PMID: 8453944].
Silva, M.F.; Aires, C.C.; Luis, P.B.; Ruiter, J.P.; IJlst, L.; Duran, M.; Wanders, R.J.; Tavares de Almeida, I. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J. Inherit. Metab. Dis., 2008, 31(2), 205-216. [ 1007/s10545-008-0841-x]. [PMID: 18392741].
Abbott, F.S.; Anari, M.R. Chemistry and Biotransformation. Milestones in Drug Therapy: Valproate; Löscher, W. , Ed.; Birkhauser Verlag:; Basel, 1999, pp. 47-75.
Sadeque, A.J.; Fisher, M.B.; Korzekwa, K.R.; Gonzalez, F.J.; Rettie, A.E. Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. J. Pharmacol. Exp. Ther., 1997, 283(2), 698-703. [PMID: 9353388].
Kiang, T.K.; Ho, P.C.; Anari, M.R.; Tong, V.; Abbott, F.S.; Chang, T.K. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol. Sci., 2006, 94(2), 261-271. []. [PMID: 16945988].
Strassburg, C.P.; Strassburg, A.; Kneip, S.; Barut, A.; Tukey, R.H.; Rodeck, B.; Manns, M.P. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut, 2002, 50(2), 259-265. []. [PMID: 11788570].
Ginsberg, G.; Hattis, D.; Sonawane, B.; Russ, A.; Banati, P.; Kozlak, M.; Smolenski, S.; Goble, R. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol. Sci., 2002, 66(2), 185-200. []. [PMID: 11896285].
Reith, D.M.; Andrews, J.; Parker-Scott, S.; Eadie, M.J. Urinary excretion of valproate metabolites in children and adolescents. Biopharm. Drug Dispos., 2000, 21(8), 327-330. [ 1002/bdd.247]. [PMID: 11514952].
Ponchaut, S.; van Hoof, F.; Veitch, K. In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions. Biochem. Pharmacol., 1992, 43(11), 2435-2442. []. [PMID: 1610408].
Stewart, C.F.; Hampton, E.M. Effect of maturation on drug disposition in pediatric patients. Clin. Pharm., 1987, 6(7), 548-564. [PMID: 3319364].
Zhou, S.F.; Zhou, Z.W.; Huang, M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology, 2010, 278(2), 165-188. []. [PMID: 19715737].
Kurose, K.; Sugiyama, E.; Saito, Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab. Pharmacokinet., 2012, 27(1), 9-54. []. [PMID: 22123129].
Hirota, T.; Eguchi, S.; Ieiri, I. Impact of genetic polymorphisms in CYP2C9 and CYP2C19 on the pharmacokinetics of clinically used drugs. Drug Metab. Pharmacokinet., 2013, 28(1), 28-37. [http://]. [PMID: 23165865].
Gotoh, O. Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J. Biol. Chem., 1992, 267(1), 83-90. [PMID: 1730627].
Crespi, C.L.; Miller, V.P. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics, 1997, 7(3), 203-210. []. [PMID: 9241660].
Wei, L.; Locuson, C.W.; Tracy, T.S. Polymorphic variants of CYP2C9: mechanisms involved in reduced catalytic activity. Mol. Pharmacol., 2007, 72(5), 1280-1288. [ mol.107.036178]. [PMID: 17686967].
Ho, P.C.; Abbott, F.S.; Zanger, U.M.; Chang, T.K. Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Pharmacogenomics J., 2003, 3(6), 335-342. []. [PMID: 14597963].
Tan, L.; Yu, J.T.; Sun, Y.P.; Ou, J.R.; Song, J.H.; Yu, Y. The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin. Neurol. Neurosurg., 2010, 112(4), 320-323. [http://]. [PMID: 20089352].
Tóth, K.; Bűdi, T.; Kiss, Á.; Temesvári, M.; Háfra, E.; Nagy, A.; Szever, Z.; Monostory, K. Phenoconversion of CYP2C9 in epilepsy limits the predictive value of CYP2C9 genotype in optimizing valproate therapy. Per. Med., 2015, 12(3), 199-207. [http://dx.doi. org/10.2217/pme.14.82]. [PMID: 29771647].
Tanaka, E. Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J. Clin. Pharm. Ther., 1999, 24(2), 87-92. []. [PMID: 10380060].
Amini-Shirazi, N.; Ghahremani, M.H.; Ahmadkhaniha, R.; Mandegary, A.; Dadgar, A.; Abdollahi, M.; Shadnia, S.; Pakdaman, H.; Kebriaeezadeh, A. Influence of CYP2C9 polymorphism on metabolism of valproate and its hepatotoxin metabolite in Iranian patients. Toxicol. Mech. Methods, 2010, 20(8), 452-457. [http://dx.]. [PMID: 20602621].
Levy, R.H.; Rettenmeier, A.W.; Anderson, G.D.; Wilensky, A.J.; Friel, P.N.; Baillie, T.A.; Acheampong, A.; Tor, J.; Guyot, M.; Loiseau, P. Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin. Pharmacol. Ther., 1990, 48(3), 225-235. []. [PMID: 2119269].
Star, K.; Edwards, I.R.; Choonara, I. Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. PLoS One, 2014, 9(10), e108970. [ journal.pone.0108970]. [PMID: 25302991].
Yu, N.; Di, Q.; Hu, Y.; Zhang, Y.F.; Su, L.Y.; Liu, X.H.; Li, L.C. A meta-analysis of pro-inflammatory cytokines in the plasma of epileptic patients with recent seizure. Neurosci. Lett., 2012, 514(1), 110-115. []. [PMID: 22402188].
Uludag, I.F.; Bilgin, S.; Zorlu, Y.; Tuna, G.; Kirkali, G. Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure, 2013, 22(6), 457-461. [http://dx.doi. org/10.1016/j.seizure.2013.03.004]. [PMID: 23566695].
Aitken, A.E.; Morgan, E.T. Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab. Dispos., 2007, 35(9), 1687-1693. []. [PMID: 17576808].
Pascussi, J.M.; Gerbal-Chaloin, S.; Pichard-Garcia, L.; Daujat, M.; Fabre, J.M.; Maurel, P.; Vilarem, M.J. Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem. Biophys. Res. Commun., 2000, 274(3), 707-713. [ 1006/bbrc.2000.3219]. [PMID: 10924340].
Pascussi, J.M.; Dvorák, Z.; Gerbal-Chaloin, S.; Assenat, E.; Maurel, P.; Vilarem, M.J. Pathophysiological factors affecting CAR gene expression. Drug Metab. Rev., 2003, 35(4), 255-268. [http://]. [PMID: 14705859].
Monostory, K.; Pascussi, J.M. Regulation of drug-metabolizing human cytochrome P450s. Acta Chim. Slov., 2008, 55, 20-37.
Pascussi, J.M.; Gerbal-Chaloin, S.; Duret, C.; Daujat-Chavanieu, M.; Vilarem, M.J.; Maurel, P. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu. Rev. Pharmacol. Toxicol., 2008, 48, 1-32. [http://]. [PMID: 17608617].
Kobayashi, K.; Hashimoto, M.; Honkakoski, P.; Negishi, M. Regulation of gene expression by CAR: an update. Arch. Toxicol., 2015, 89(7), 1045-1055. []. [PMID: 25975989].
Prakash, C.; Zuniga, B.; Song, C.S.; Jiang, S.; Cropper, J.; Park, S.; Chatterjee, B. Nuclear Receptors in drug metabolism, drug response and drug interactions. Nucl. Receptor Res., 2015, 2, 101178. []. [PMID: 27478824].
Anderson, G.D. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia, 2002, 43(Suppl. 3), 53-59. [http://]. [PMID: 12060006].
Nagy, A.; Bűdi, T.; Temesvári, M.; Szever, Z.; Szabó, P.T.; Monostory, K. Adverse events in a newborn on valproate therapy due to loss-of-function mutations in CYP2C9. Epilepsy Behav. Case Rep., 2015, 4, 86-87. [ 08.006]. [PMID: 26543813].
Dreifuss, F.E.; Langer, D.H. Hepatic considerations in the use of antiepileptic drugs. Epilepsia, 1987, 28(Suppl. 2), S23-S29. [http://]. [PMID: 3121292].
Scheffner, D.; König, S.; Rauterberg-Ruland, I.; Kochen, W.; Hofmann, W.J.; Unkelbach, S. Fatal liver failure in 16 children with valproate therapy. Epilepsia, 1988, 29(5), 530-542. [http://dx.]. [PMID: 3137017].
Bűdi, T.; Tóth, K.; Nagy, A.; Szever, Z.; Kiss, Á.; Temesvári, M.; Háfra, E.; Garami, M.; Tapodi, A.; Monostory, K. Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia, 2015, 56(6), 849-855. [ 13011]. [PMID: 25967074].
Yamamoto, Y.; Takahashi, Y.; Suzuki, E.; Mishima, N.; Inoue, K.; Itoh, K.; Kagawa, Y.; Inoue, Y. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res., 2012, 101(3), 202-209. [ j.eplepsyres.2012.04.001]. [PMID: 22542569].
Yamamoto, Y.; Takahashi, Y.; Imai, K.; Mishima, N.; Yazawa, R.; Inoue, K.; Itoh, K.; Kagawa, Y.; Inoue, Y. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia, 2013, 54(6), 983-989. []. [PMID: 23409971].
Tseng, Y.L.; Huang, C.R.; Lin, C.H.; Lu, Y.T.; Lu, C.H.; Chen, N.C.; Chang, C.C.; Chang, W.N.; Chuang, Y.C. Risk factors of hyperammonemia in patients with epilepsy under valproic acid therapy. Medicine (Baltimore), 2014, 93(11), e66. [http://dx.doi. org/10.1097/MD.0000000000000066]. [PMID: 25192484].
Monostory, K.; Bűdi, T.; Tóth, K.; Nagy, A.; Szever, Z.; Kiss, Á.; Temesvári, M.; Háfra, E.; Tapodi, A.; Garami, M. In response: Commentary on clinical significance of CYP2C9-status-guided valproic acid therapy in children. Epilepsia, 2016, 57(8), 1339-1340. []. [PMID: 27485380].

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [99 - 106]
Pages: 8
DOI: 10.2174/1570159X15666171109143654

Article Metrics

PDF: 48