Editing Valproate (section)

==Pharmacology==
===Pharmacodynamics===
Although the mechanism of action of valproate is not fully understood,<ref name = TGA/> traditionally, its anticonvulsant effect has been attributed to the blockade of [[voltage-gated sodium channel]]s and increased brain levels of the inhibitory synaptic neurotransmitter [[Gamma-Aminobutyric acid|gamma-aminobutyric acid]] (GABA).<ref name = TGA/> The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.<ref name = TGA/> In animals, sodium valproate raises cerebral and cerebellar levels of GABA, possibly by inhibiting GABA degradative enzymes, such as [[GABA transaminase]], [[succinate-semialdehyde dehydrogenase]] and by inhibiting the re-uptake of GABA by neuronal cells.<ref name = TGA/>
Prevention of neurotransmitter-induced hyperexcitability of nerve cells via [[KvLQT2|Kv7.2 channel]] and [[AKAP5]] may also contribute to its mechanism.<ref>{{cite journal | vauthors = Kay HY, Greene DL, Kang S, Kosenko A, Hoshi N | title = M-current preservation contributes to anticonvulsant effects of valproic acid | journal = The Journal of Clinical Investigation | volume = 125 | issue = 10 | pages = 3904–3914 | date = October 2015 | pmid = 26348896 | pmc = 4607138 | doi = 10.1172/JCI79727 }}</ref> Valproate has been shown to protect against a seizure-induced reduction in [[phosphatidylinositol (3,4,5)-trisphosphate]] (PIP3) as a potential therapeutic mechanism.<ref>{{cite journal | vauthors = Chang P, Walker MC, Williams RS | title = Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid | journal = Neurobiology of Disease | volume = 62 | pages = 296–306 | date = February 2014 | pmid = 24148856 | pmc = 3898270 | doi = 10.1016/j.nbd.2013.10.017 }}</ref>

Valproate is a [[histone deacetylase inhibitor]]. By inhibition of [[histone deacetylase]], it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation.<ref>{{cite journal | vauthors = Sakai K, Hara K, Tanemura K | title = Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation | journal = PLOS ONE | volume = 18 | issue = 3 | pages = e0282898 | date = 3 September 2023 | pmid = 36893188 | pmc = 9997898 | doi = 10.1371/journal.pone.0282898 | doi-access = free | bibcode = 2023PLoSO..1882898S }}</ref> Intermediate molecules include [[VEGF]], [[BDNF]], and [[GDNF]].<ref>{{cite journal | vauthors = Kostrouchová M, Kostrouch Z, Kostrouchová M | title = Valproic acid, a molecular lead to multiple regulatory pathways | journal = Folia Biologica | volume = 53 | issue = 2 | pages = 37–49 | year = 2007 | doi = 10.14712/fb2007053020037 | pmid = 17448293 | url = http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf | url-status = dead | access-date = 13 February 2014 | archive-url = https://web.archive.org/web/20140221230758/http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf | archive-date = 21 February 2014 }}</ref><ref name="Therapeutic potential of mood stabi">{{cite journal | vauthors = Chiu CT, Wang Z, Hunsberger JG, Chuang DM | title = Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder | journal = Pharmacological Reviews | volume = 65 | issue = 1 | pages = 105–142 | date = January 2013 | pmid = 23300133 | pmc = 3565922 | doi = 10.1124/pr.111.005512 | author4-link = De-Maw Chuang }}</ref>

====Endocrine actions====
Valproic acid has been found to be an [[receptor antagonist|antagonist]] of the [[androgen receptor|androgen]] and [[progesterone receptor]]s, and hence as a [[nonsteroidal]] [[antiandrogen]] and [[antiprogestogen]], at concentrations much lower than therapeutic serum levels.<ref name="pmid16165177">{{cite journal | vauthors = Death AK, McGrath KC, Handelsman DJ | title = Valproate is an anti-androgen and anti-progestin | journal = Steroids | volume = 70 | issue = 14 | pages = 946–953 | date = December 2005 | pmid = 16165177 | doi = 10.1016/j.steroids.2005.07.003 | s2cid = 25958985 | hdl = 10453/16875 | hdl-access = free }}</ref> In addition, the drug has been identified as a potent [[aromatase inhibitor]], and suppresses [[estrogen]] concentrations.<ref name="WyllieCascino2012">{{cite book|vauthors=Wyllie E, Cascino GD, Gidal BE, Goodkin HP|title=Wyllie's Treatment of Epilepsy: Principles and Practice|url=https://books.google.com/books?id=j9t6Qg0kkuUC&pg=PA288-IA37|date=17 February 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-5348-4|pages=288–|url-status=live|archive-url=https://web.archive.org/web/20140606200832/http://books.google.com/books?id=j9t6Qg0kkuUC|archive-date=6 June 2014}}</ref> These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.<ref name="pmid16165177" /><ref name="WyllieCascino2012" />

Valproic acid has been found to directly stimulate androgen biosynthesis in the [[gonad]]s via inhibition of histone deacetylases and has been associated with [[hyperandrogenism]] in women and increased [[4-androstenedione]] levels in men.<ref name="UchidaMaruyama2005">{{cite journal | vauthors = Uchida H, Maruyama T, Arase T, Ono M, Nagashima T, Masuda H, Asada H, Yoshimura Y | title = Histone acetylation in reproductive organs: Significance of histone deacetylase inhibitors in gene transcription | journal = Reproductive Medicine and Biology | volume = 4 | issue = 2 | pages = 115–122 | date = June 2005 | pmid = 29662388 | pmc = 5891791 | doi = 10.1111/j.1447-0578.2005.00101.x }}</ref><ref name="IsojärviTaubøll2005">{{cite journal | vauthors = Isojärvi JI, Taubøll E, Herzog AG | title = Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy | journal = CNS Drugs | volume = 19 | issue = 3 | pages = 207–223 | year = 2005 | pmid = 15740176 | doi = 10.2165/00023210-200519030-00003 | s2cid = 9893959 }}</ref> High rates of [[polycystic ovary syndrome]] and [[menstrual disorder]]s have also been observed in women treated with valproic acid.<ref name="IsojärviTaubøll2005" />

===Pharmacokinetics===
[[File:Valproic acid metabolism.svg|class=skin-invert-image|upright=1.5|thumb|250px|Some [[metabolites]] of valproic acid. [[Glucuronidation]] and [[β-oxidation]] are the main metabolic pathways; [[ω-oxidation]] metabolites are considered [[hepatotoxic]].<ref name="AC">{{cite book|title=Austria-Codex|veditors = Haberfeld H|at=Depakine chrono retard 300 mg Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}</ref><ref>{{cite journal | vauthors = Kumar S, Wong H, Yeung SA, Riggs KW, Abbott FS, Rurak DW | title = Disposition of valproic acid in maternal, fetal, and newborn sheep. II: metabolism and renal elimination | journal = Drug Metabolism and Disposition | volume = 28 | issue = 7 | pages = 857–864 | date = July 2000 | doi = 10.1016/S0090-9556(24)15356-1 | pmid = 10859160 }}</ref> Details see text.]]

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.<ref name="AC" /> When in the bloodstream, 80–90% of the substance are bound to [[plasma protein]]s, mainly [[albumin]]. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as [[aspirin]], as well as liver and kidney impairment.<ref>{{cite book|title=Angewandte Arzneimitteltherapie | veditors = Schneemann H, Young L, Koda-Kimble MA |publisher=Springer |language=de |year=2001 |isbn=3-540-41356-1 |pages=28–29}}</ref><ref name="Drugs.com">Valproate {{Drugs.com|pro|valproate}}. Accessed 6 August 2021.</ref> Concentrations in the [[cerebrospinal fluid]] and in breast milk are 1 to 10% of blood plasma concentrations.<ref name="AC" />

The vast majority of valproate [[Drug metabolism|metabolism]] occurs in the [[liver]].<ref name="Drugbank-Valproate" /> Valproate is known to be metabolized by the [[cytochrome P450]] enzymes [[CYP2A6]], [[CYP2B6]], [[CYP2C9]], and [[CYP3A5]].<ref name="Drugbank-Valproate" /> It is also known to be metabolized by the [[UDP-glucuronosyltransferase]] enzymes [[UGT1A3]], [[UGT1A4]], [[UGT1A6]], [[UGT1A8]], [[UGT1A9]], [[UGT1A10]], [[UGT2B7]], and [[UGT2B15]].<ref name="Drugbank-Valproate" />  Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):<ref name="Drugbank-Valproate" />
* via [[glucuronidation]] (30–50%): valproic acid β-O-[[glucuronide]]
* via [[beta oxidation]] (>40%): 2''E''-ene-valproic acid, 2''Z''-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
* via [[omega oxidation]]: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
* some others: 3''E''-ene-valproic acid, 3''Z''-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid
All in all, over 20 metabolites are known.<ref name="AC" />

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in [[urine]] as the glucuronide conjugate.<ref name="Drugbank-Valproate" />  The other major pathway in the metabolism of valproate is [[mitochondria]]l beta oxidation, which typically accounts for over 40% of an administered dose.<ref name="Drugbank-Valproate" /> Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.<ref name="Drugbank-Valproate" /> Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.<ref name="Drugbank-Valproate">{{cite web | title=Valproic Acid | url=https://www.drugbank.ca/drugs/DB00313#pharmacology | work=DrugBank | publisher=University of Alberta | date=31 August 2017 | access-date=1 September 2017 | archive-date=31 July 2017 | archive-url=https://web.archive.org/web/20170731023353/https://www.drugbank.ca/drugs/DB00313#pharmacology | url-status=live }}</ref> Only a small amount is excreted via the faeces.<ref name="AC" /> [[Elimination half-life]] is 16±3 hours and can decrease to 4–9 hours when combined with [[enzyme inducer]]s.<ref name="AC" /><ref name="Drugs.com" />