Effects of Lithium on the Pharmacokinetics of Valproate in Rats

Yoshioka, Hiroshi; Ida, Seiko; Yokota, Masayuki; Nishimoto, Ayako; Shibata, Sachiko; Sugawara, Akiko; Takiguchi, Yoshiharu

doi:10.1211/0022357001773986

Cited by 12 publications

(6 citation statements)

References 14 publications

(12 reference statements)

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“…In this study, the pharmacokinetic profiles of single-treatment VPA were similar to the findings of Yoshioka et al31, who showed that soy has a significant effect on the C max of VPA but not on t max value (Figure 1). Analysis of urine excreted 0–24 h after VPA consumption provided a much clearer view of the effect of soy (Figure 2A).…”

Section: Discussionsupporting

confidence: 89%

Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

Marahatta

Bhandary

Jeong

et al. 2014

Sci Rep

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The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.

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Section: Discussionsupporting

confidence: 89%

Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

Marahatta

Bhandary

Jeong

et al. 2014

Sci Rep

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“…The far greater efficacy of simultaneous polytherapy over sequential monotherapies at the same dose is compatible with increasing pharmacoresistance, associated with seizure-induced increases in receptor trafficking, during the delay between sequential drug injections. However, because of the short half-lives of drugs in rats, only 40–50% of injected midazolam would be expected to remain in plasma when valproate is injected (Bittner et al, 2003), and about 60% of injected valproate would be in circulation at the time of ketamine injection (Yoshioka et al, 2000) limiting interactions between sequential drugs. The improvement in outcome when adding low-dose valproate (which was ineffective when given alone) to ketamine and midazolam may reflect the inability of benzodiazepines to fully restore inhibition when treatment is delayed and many synaptic GABA A R are internalized, and the need to enhance inhibition at a non-benzodiazepine site when treatment is delayed and benzodiazepine pharmacoresistance is high.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous triple therapy for the treatment of status epilepticus

Niquet

Baldwin

Norman

et al. 2017

Neurobiology of Disease

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Early maladaptive internalization of synaptic GABAA receptors (GABAA R) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

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“…Blood valproic acid levels were 42 Ϯ 6 mg/l. This level may not reflect the average daily level of valproic acid because the half-life of valproic acid is Ͻ0.5 hr in rats (Yoshioka et al, 2000;Stout et al, 2001).…”

Section: Methodsmentioning

confidence: 98%

Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis

Hao¹,

Creson²,

Zhang³

et al. 2004

J. Neurosci.

377

300

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Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproateinduced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.

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Effects of Lithium on the Pharmacokinetics of Valproate in Rats

Cited by 12 publications

References 14 publications

Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

Simultaneous triple therapy for the treatment of status epilepticus

Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis

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