Editing Valproate (section)

===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" />