The Free Fraction of Valproic Acid in Tears, Saliva, and Cerebrospinal Fluid

Monaco, Francesco; Piredda, S.; Mutani, Roberto; Mastropaolo, C; Tondi, M.

doi:10.1111/j.1528-1157.1982.tb05049.x

Cited by 36 publications

(14 citation statements)

References 7 publications

(3 reference statements)

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“…It is doubtful whether the binding of VPA is influenced by other AEDs (30). Unbound VPA concentrations in serum approximate those in CSF and tears (63,94).…”

Section: Protein Bindingmentioning

confidence: 99%

Valproate: Past, Present, and Future

2003

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Preclinical studies have been carried out during the past four decades to investigate the different mechanisms of action of valproate (VPA). The mechanisms of VPA which seem to be of clinical importance include increased GABAergic activity, reduction in excitatory neurotransmission, and modification of monoamines. These mechanisms are discussed in relation to the various clinical uses of the drug. VPA is widely used as an antiepileptic drug with a broad spectrum of activity. In patients, VPA possesses efficacy in the treatment of various epileptic seizures such as absence, myoclonic, and generalized tonicclonic seizures. It is also effective in the treatment of partial seizures with or without secondary generalization and acutely in status epilepticus.The pharmacokinetic aspects of VPA and the frequent drug interactions between VPA and other drugs are discussed. The available methods for the determination of VPA in body fluids are briefly evaluated.At present, investigations and clinical trials are carried out and evaluated to explore the new indications for VPA in other conditions such as in psychiatric disorders, migraine and neuropathic pain. Furthermore, the toxicity of VPA, both regarding commonly occurring side effects and potential idiosyncratic reactions are described. Derivatives of VPA with improved efficacy and tolerability are in development.

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“…It is doubtful whether the binding of VPA is influenced by other AEDs (30). Unbound VPA concentrations in serum approximate those in CSF and tears (63,94).…”

Section: Protein Bindingmentioning

confidence: 99%

Valproate: Past, Present, and Future

2003

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“…Marked inter-and intraindividual varia tion in the saliva/plasma total valproic acid concentration ratio (between 0.5 and 4.9) were reported using gas-liquid chromatogra phy and EMIT techniques [107][108][109][110], but much less variability was described using a highly sensitive methodology (gas chromatog raphy-mass spectrometry) [106], however only 12 infants recommended saliva for therapeutic drug monitoring of digoxin [112]. Many studies indicate that better correla tions in drug concentrations between saliva and plasma are obtained using the clear super natant of stimulated saliva specimens col lected not earlier than 2 h after the dose, as compared with untimed, unspun resting sali va. As discussed earlier, stimulation of saliva secretion offers several advantages in the clin ical use of saliva for monitoring drug therapy.…”

Section: Carbamazepine (Table 2)mentioning

confidence: 99%

Salivary Excretion of Drugs in Children: Theoretical and Practical Issues in Therapeutic Drug Monitoring

Gorodischer

Koren²

1992

Dev Pharmacol Ther

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Studies suggest that saliva could be used instead of blood in the therapeutic monitoring of many drugs. This has distinct advantages in pediatrics and neonatology as saliva sampling is painless and spares blood. Stimulation of saliva secretion with a chemical stimulus (i.e. citric acid applied over the tongue) facilitates the study of younger patients. Secretory and reabsorptive processes which take place in the ductal system of the salivary glands, and the rate of flow of the secretion play major roles in the determination of the concentration of solutes in saliva. Drug passage into saliva follows the general principles of movement of drugs across biologic membranes. Only the unbound fraction of the drug in plasma is available for diffusion into saliva and a relationship exists between saliva pH and the saliva/plasma concentration ratio of many polar drugs (tolbutamide, propranolol, procainamide, etc.). However, deviations from the pH theory exist and the inter- and intraindividual variations in saliva/plasma concentration ratios of salicylate and procainamide cannot be explained solely on the basis of fluctuations of salivary pH; on the other hand, a useful relationship exists between plasma and saliva phenobarbital concentrations with no need to correct for saliva pH. The use of stimulated saliva has several advantages over resting saliva: a larger volume of the sample is obtained, the pH gradient between plasma and saliva is smaller, the variability in saliva/plasma concentration ratios of some drugs is narrowed, and less specimens are too viscous or discolored to allow drug analysis. Thorough rinsing of the mouth is required prior to saliva sampling as remnants of orally administered medicines may contaminate saliva specimens and give spuriously high values. Deviation from a simple but strict methodology accounts for some of the discrepancies found in the literature. Studies in children uniformly recommend saliva for therapeutic monitoring of phenytoin, carbamazepine and phenobarbital. Saliva sampling for theurapeutic monitoring of ethosuximide, primidone and digoxin in infants and children, and of theophylline and caffeine in the neonate is promising, but little pediatric experience is available as yet. The value of saliva in therapeutic monitoring of theophylline in children is still controversial. Little of highly polar compounds such as aminoglycosides, and of polar highly protein bound drugs such as valproic acid is present in saliva. More data are still needed on the excretion of drugs in saliva in infants and in acutely ill children, and few data exist in the premature and full-term neonate.

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“…[20][21][22][23][24] Free plasma VPA levels seem to correlate with free CSF and tear levels. 25 Saliva-free concentrations do not correlate well with free plasma levels and are unreliable.…”

Section: Can the Drug Be Readily Measured In The Desired Biologic Matmentioning

confidence: 88%

Does Valproic Acid Warrant Therapeutic Drug Monitoring in Bipolar Affective Disorder?

Haymond¹,

Ensom²

2010

Therapeutic Drug Monitoring

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To review the pharmacokinetic literature regarding valproic acid (VPA) in patients with bipolar affective disorder to evaluate the appropriateness of routine therapeutic drug monitoring (TDM) of VPA in this population. Embase, Medline, Biosis, Cumulated Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Systematic Reviews databases (to July 2009) were searched (terms: valproate, valproic acid, valproate semisodium, divalproex, bipolar disorder, mania, bipolar affective disorder, assay, concentration, drug level, serum level, plasma level, therapeutic drug monitoring, drug monitoring, pharmacokinetics). A 9-step decision-making algorithm was applied to the available VPA literature in the bipolar population. VPA has been established as effective first-line therapy in the treatment of bipolar mania. Commercial assays are available to accurately measure VPA levels with good sensitivity and precision. Wide interpatient variability in VPA pharmacokinetic parameters and long anticipated treatment durations favor the use of TDM in the bipolar patient. Conversely, correlations between VPA levels and pharmacologic response in humans, and specifically patients with bipolar affective disorder are unclear. Compared with other agents known to have narrow therapeutic ranges, VPA does not seem to share this characteristic. Furthermore, the clinical efficacy and toxicity of VPA may be assessed in ways other than TDM, allowing for contributions by health care professionals, patients, and family members. Despite the development of effective and widely available VPA assays, routine monitoring of VPA concentrations in the general bipolar affective population does not seem warranted. However, TDM may enhance usual clinical monitoring in situations involving unusual VPA metabolism, polytherapy with clinically relevant drug interactions, or as part of a comprehensive assessment of treatment compliance.

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The Free Fraction of Valproic Acid in Tears, Saliva, and Cerebrospinal Fluid

Cited by 36 publications

References 7 publications

Valproate: Past, Present, and Future

Valproate: Past, Present, and Future

Salivary Excretion of Drugs in Children: Theoretical and Practical Issues in Therapeutic Drug Monitoring

Does Valproic Acid Warrant Therapeutic Drug Monitoring in Bipolar Affective Disorder?

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