Small Effects of Valproic Acid on the Plasma Concentrations of Clozapine and its Major Metabolites in Patients With Schizophrenic or Affective Disorders

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 μg/mL, which was only slightly above the recommended therapeutic range (50–100 μg/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 μg/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

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Possible Mechanism by Which the Carbapenem Antibiotic Panipenem Decreases the Concentration of Valproic Acid in Plasma in Rats

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.12.3136 ◽

1998 ◽

Vol 42 (12) ◽

pp. 3136-3140 ◽

Cited By ~ 37

Author(s):

Saori Kojima ◽

Masayuki Nadai ◽

Kiyoyuki Kitaichi ◽

Li Wang ◽

Toshitaka Nabeshima ◽

...

Keyword(s):

Valproic Acid ◽

Body Weight ◽

Bile Duct ◽

Plasma Concentrations ◽

Enteric Bacteria ◽

Enterohepatic Recirculation ◽

Constant Infusion ◽

Initial Space ◽

Induced Changes ◽

Carbapenem Antibiotic

ABSTRACT There is evidence indicating that the carbapenem antibiotic panipenem decreases plasma concentrations of valproic acid (VPA) in epileptic patients during VPA therapy. The mechanism for panipenem-induced changes in the pharmacokinetics of VPA was investigated in rats with and without bile duct cannulation. The effect of panipenem on the pharmacokinetics of diclofenac, which undergoes extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of body weight) or diclofenac (10 mg/kg of body weight) was administered intravenously under the steady-state plasma panipenem concentration of 4 μg/ml, which had been achieved by a constant infusion rate. Panipenem decreased the plasma VPA concentrations in rats without bile duct cannulation but did not change the volume of the initial space and protein binding of VPA. However, panipenem had no effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in plasma diclofenac concentration observed in the absence of panipenem was diminished in the presence of panipenem. These findings suggest that panipenem decreases plasma VPA concentrations by suppressing its enterohepatic recirculation, probably due to a panipenem-induced decrease in the numbers of enteric bacteria.

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Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury

Scandinavian Journal of Trauma Resuscitation and Emergency Medicine ◽

10.1186/s13049-017-0382-0 ◽

2017 ◽

Vol 25 (1) ◽

Cited By ~ 4

Author(s):

Yirui Sun ◽

Jian Yu ◽

Qiang Yuan ◽

Xing Wu ◽

Xuehai Wu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Valproic Acid ◽

Brain Injury ◽

Genetic Polymorphisms ◽

Severe Traumatic Brain Injury ◽

Plasma Concentrations ◽

Post Traumatic

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

Scientific Reports ◽

10.1038/srep04362 ◽

2014 ◽

Vol 4 (1) ◽

Cited By ~ 10

Author(s):

Anu Marahatta ◽

Bidur Bhandary ◽

Seul-Ki Jeong ◽

Hyung-Ryong Kim ◽

Han-Jung Chae

Keyword(s):

Valproic Acid ◽

Drug Interaction ◽

Plasma Concentrations ◽

Interaction Study ◽

Drug Interaction Study

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187 Early Post-Traumatic Seizures are Associated with Valproic Acid Plasma Concentrations and UGT1A6/CYP2C9 Genetic Polymorphisms in Patients with Severe Traumatic Brain Injury

Neurosurgery ◽

10.1093/neuros/nyx417.187 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 249-250

Author(s):

Yirui Sun ◽

Jian Yu ◽

Qiang Yuan ◽

Jin Hu

Keyword(s):

Traumatic Brain Injury ◽

Valproic Acid ◽

Brain Injury ◽

Genetic Polymorphisms ◽

Severe Traumatic Brain Injury ◽

Plasma Concentrations ◽

Eeg Monitoring ◽

Continuous Eeg ◽

Severe Tbi ◽

Post Traumatic

Abstract INTRODUCTION Seizure is a common complication for severe traumatic brain injury (TBI). Valproic acid (VPA) is a first-line antiepileptic drug, though its metabolism is affected by genetic polymorphisms and varies between individuals. The aim of this study was to investigate such association and to explore its influence on the occurrence of early post-traumatic seizure. METHODS A case control study was conducted from 2012 to 2016 recruiting adult patients with severe TBI. Continuous electroencephalograph (EEG) monitoring was performed for 7 days. Genetic polymorphisms in UGT1A6, UGT2B7, CYP2C9, and CYP2C19 were analyzed in association with daily VPA plasma concentrations, adjusted dosages, and occurrence seizures. RESULTS >Among the 395 recruited patients, eight-three (21%) had early post-traumatic seizure, of which 30 (36.14%) were non-convulsive. Most seizures were first detected on day 1 (34.94%) and day 2 (46.99%) after injury. Patients with seizure had longer ICU length of stay and relatively lower VPA plasma concentrations. Patients with UGT1A6_19T>G/541A>G/552A>C double heterozygosities or CYP2C9 extensive metabolizers (EMs) initially had lower adjusted VPA plasma concentrations (power >0.99) and accordingly require higher VPA dosages during later time of treatment (power >0.99). The odds ratio indicated a higher risk of early post-traumatic seizure occurrence in male patients (OR 1.96, 95% CI 1.01-3.81, P = 0.043), age over 65 (OR 2.13, 95% CI 1.01-4.48), and with UGT1A6_19T>G/541A>G/552A>C double heterozygosities (OR 2.38, 95% CI 1.11-5.10, P = 0.02). CONCLUSION Continuous EEG monitoring are necessary to detect both convulsive and non-convulsive early post-traumatic seizures in severe TBI patients. UGT1A6/CYP2C9 polymorphisms have influence on VPA metabolism. UGT1A6_19T>G/541A>G/552A>C double heterozygositie is associated with occurrence of early post-traumatic seizures in addition to patients' age and gender. Further investigations with larger sample size are required to confirm the difference.

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