Contribution of CYP2C9, CYP2A6, and CYP2B6 to Valproic Acid Metabolism in Hepatic Microsomes from Individuals with the CYP2C9*1/*1 Genotype

Kiang, Tony K. L.; Ho, Ping C.; Anari, M. Reza; Tong, Vincent; Abbott, Frank S.; Chang, Thomas K. H.

doi:10.1093/toxsci/kfl096

Cited by 141 publications

(104 citation statements)

References 28 publications

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“…VPA is metabolized primarily by conjugation with glucuronic acid or carnitine, and to a lesser extent by mitochondrial ␤-oxidation, microsomal -oxidation, and -1-oxidation (Zaccara et al, 1988). Microsomal VPA metabolism has been shown to be catalyzed by various cytochrome P450 isozymes, among them CYP2C9, CYP2A6, and CYP2B6 (Kiang et al, 2006). These oxidative pathways can yield potentially hepatotoxic products, e.g., pentanoate and propionate, as well as 4-ene-VPA and others.…”

Section: Discussionmentioning

confidence: 99%

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Knapp

Todesco²,

Beier³

et al. 2007

J Pharmacol Exp Ther

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The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs) ϩ/Ϫ mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs ϩ/Ϫ mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs ϩ/Ϫ mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of L-glutamate, succinate, and palmitate, as well as ␤-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs ϩ/Ϫ mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs ϩ/Ϫ mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wildtype mice and jvs ϩ/Ϫ mice) and tissue levels (jvs ϩ/Ϫ mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs ϩ/Ϫ mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wildtype mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.

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Section: Discussionmentioning

confidence: 99%

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Knapp

Todesco²,

Beier³

et al. 2007

J Pharmacol Exp Ther

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“…The physician reported a reduced half-life of valproic acid, whereas the half-life of carbamazepine did not change, thereby indicating that mefloquine may have specifically accelerated valproic acid metabolism. While carbamazepine is metabolized mainly by CYP3A4 (41), whose activity is not induced in vivo by mefloquine (27,36), valproic acid has been shown to be metabolized by CYP2A6, CYP2B6, and CYP2C9 (42). Thus, the induction of hepatic CYP2B6 by carboxymefloquine may explain the observation.…”

Section: Discussionmentioning

confidence: 99%

Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor

Piedade

Traub

Bitter

et al. 2015

Antimicrob Agents Chemother

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f Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies. M alaria, which is caused by infection with parasitic protozoans of the genus Plasmodium, is still a major global health burden, with an estimated 207 million cases and 627,000 deaths worldwide in 2012 (1). The emerging resistance of the parasite to artemisinins (2) and the need to treat malaria patients coinfected with HIV and/or mycobacteria causing tuberculosis (3) increasingly necessitates the use of combination drug therapies and coadministration of drugs, respectively, which also may be accompanied by a higher risk for drug-drug interactions. Mechanistically, these may arise from the inhibition or induction of metabolism and/or transport of coadministered drugs. Competitive or noncompetitive enzyme inhibition may result in adverse toxic effects due to higher-than-expected drug concentrations, whereas clinically relevant induction may result in therapeutic failure due to insufficient drug levels. The interaction potential of antimalarial drugs due to the inhibition of cytochrome P450 (CYP) drugmetabolizing enzymes has been analyzed quite extensively in vitro, and it has been shown to result in some clinically relevant drugdrug interactions, as exemplified...

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“…CYP2C9*1 is the predominant catalyst in the formation of 4-ene-VPA (a toxic metabolite of VPA), 4-OH-VPA, and 5-OH-VPA. CYP2A6 contributes partially to 3-OH-VPA formation [79]. CBZ and OXC are inducers of drug metabolism via CYP3A4.…”

Section: -1 Aed-related Cypsmentioning

confidence: 99%

Individualized Medicine for Epilepsy -Based on Genetic Information-

Yoshida

Saruwatari

Chen

et al. 2010

E&S

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Contribution of CYP2C9, CYP2A6, and CYP2B6 to Valproic Acid Metabolism in Hepatic Microsomes from Individuals with the CYP2C91/1 Genotype

Cited by 141 publications

References 28 publications

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor

Individualized Medicine for Epilepsy -Based on Genetic Information-

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