Valproic acid pathway

Abstract

Valproic acid (VPA) is a branched short-chain fatty acid derived from naturally occurring valeric acid. VPA is used primarily in the treatment of epilepsy and seizures, but is also used in migraine, bipolar, mood, anxiety, and psychiatric disorders [1]. Recent work has explored its use as an adjuvant agent in cancer, HIV therapy, and neurodegenerative disease because of its action as histone deacetylase (HDAC) inhibitor [2]. VPA is widely used in pediatric epilepsy because of its multiple mechanisms of action and acceptable safety profile [3]. The dose requirements for VPA are highly variable (10-fold differences in mean dose in adults) [4] and interactions with other drugs are common (discussed below). Therapeutic drug monitoring is commonly used, although both the clinical and toxic effects of the drug are considered to be poorly correlated with total serum concentrations [3]. The drug label carries a black box warning for life-threatening adverse drug reactions (ADR) including hepatoxocity, teratogenicity, and pancreatitis [1]. Compared with adults, children appear to be at an increased risk for severe hepatotoxic reactions to VPA, in particular those younger than 2 years of age undergoing polytherapy, with existing developmental delays and coincident metabolic disorders [1]. Hyperammonemia is also a documented ADR of VPA treatment, although this is usually successfully resolved by cessation of VPA and treatment with carnitine [5]. The Food and Drug Administration has issued recommendations for patient testing and advises that VPA is contraindicated in patients with known urea cycle disorders (see Clinical PGx tab at http://www.pharmgkb.org/drug/PA451846). However, specific genetic tests for the determination of at-risk patients are not mentioned. The aim of this study was to introduce candidate genes in the pharmacokinetics (PK) (Fig. 1), pharmacodynamics (PD) of VPA (Fig. 2), and discuss results from pharmacogenomic studies so far. Fig. 1 Graphic representation of the candidate genes involved in valproic acid (VPA) pharmacokinetics. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/pathway/PA165964265. CYP, cytochrome P450. Fig. 2 Graphic representation of the candidate genes involved in valproic acid (VPA) pharmacodynamics. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/pathway/PA165959313. Pharmacokinetics VPA is highly protein bound (87–95%) resulting in low clearance (6–20 ml/h/kg) [6]. There are at least three routes of VPA metabolism in humans: glucuronidation, β oxidation in the mitochondria (both considered major routes accounting for 50 and 40% of dose, respectively), and cytochrome P450 (CYP)-mediated oxidation (considered a minor route, ~10%) [7-9]. Valproate glucuronide is the major urinary metabolite of VPA (~30–50%) [8]. In-vitro studies of human liver microsomes and purified recombinant proteins have reported glucuronidation of VPA by UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15 [8,10,11]. Other studies have disputed the role of UGT2B15, suggesting that VPA inhibits UGT2B15, but is not glucuronidated by it [12]. UGT1A1 does not have activity against VPA in vitro [8,12]. VPA is a fatty acid and can be metabolized through endogenous pathways in the mitochondria (Fig. 1). It has been observed that some of the mitochondrial metabolites of VPA generated by this pathway are hepatotoxic. The current understanding of VPA bioactivation involves the entry of 4-ene-VPA into the mitochondria, formation of a 4-ene-VPA-CoA ester with the help of ACADSB, and subsequent β-oxidation to form the reactive 2,4-diene-VPA-CoA ester [13,14]. Studies have demonstrated that the β-oxidation is blocked in fluorinated derivatives of 4-ene-VPA [15], and that the fluoro derivative of 4-ene-VPA cannot form a CoA ester [16], indicating a specific role of β oxidation of 4-ene-VPA in the formation of the 2,4-diene metabolite. This putative cytotoxic metabolite (2,4-diene-VPA-S-CoA) further gets conjugated with glutathione to form thiol conjugates. These chemically reactive metabolites generated from 4-ene-VPA have the potential to deplete mitochondrial glutathione pools [13] and form conjugates with CoA [17], in turn inhibiting enzymes in the β-oxidation pathway [18,19]. Identification of N-acetylcysteine conjugates of (E)-2,4-diene-VPA in human urine demonstrated that the reactive thiol conjugates of VPA arise primarily from the biotransformation of (E)-2,4-diene VPA in humans [20]. The key CYP-mediated branch of the VPA pathway is the generation of the metabolite 4-ene-VPA by CYP2C9, CYP2A6, and to a lesser extent by CYP2B6 [21,22]. In addition, these metabolizing enzymes also mediate the metabolism of VPA to the inactive 4-OH-VPA and 5-OH-VPA [23]. CYP2A6 also contributes partially to the formation of 3-OH-VPA [22].