Distribution of sodium valproate in normal whole blood and in blood from patients with renal or hepatic disease

Shirkey, R. J.; Jellett, L. B.; Kappatos, Diana; Maling, T. J. B.; Macdonald, Alistair

doi:10.1007/bf00544365

Cited by 20 publications

(11 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…restricted partitioning into blood cells (red blood cell/ plasma partition ratio of 0.2 in human) (31). Thus it can be deduced that the VPA concentration tested in the present in vitro interaction assay largely encompasses the concentration expected at the site of LEV hydrolysis in the clinical situation.…”

Section: Discussionmentioning

confidence: 91%

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

2003

View full text Add to dashboard Cite

Summary:Purpose: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited druginteraction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions.Methods: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, onesequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. Results:Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 g/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 g/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA.Conclusions: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during shortterm administration, and suggest that dose adjustment is not required when these two drugs are given together.

show abstract

Section: Discussionmentioning

confidence: 91%

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

2003

View full text Add to dashboard Cite

show abstract

“…It is projected that only the unbound drugs can partition into RBCs [27], [28] and that this partition is consistent at varying concentrations [29], [30]. VPA has been shown to partition into the RBC from the plasma at ratios ranging from 0.04 to 0.20 [23], [24], [29]. Since most of our patients had plasma VPA concentrations within the therapeutic ranges, and normal albumin levels, the K was presumably to be constant [29].…”

Section: Discussionmentioning

confidence: 99%

“…Theoretical C plasma was calculated using a formula which accounts for the individual hematocrit values and red blood cell-to-plasma partition (RBC/plasma) ratio [20], [21].where Hct is the individual hematocrit value and K is the RBC/plasma ratio of the AEDs. To ease clinical applicability, K was fixed at literature values of 0.29 [22] and 0.43 for PHT [20] and 0.04 [23] and 0.20 [24] for VPA. As for CBZ, its theoretical plasma concentration approaches that of C dbs , rendering the effect of Hct on computation of theoretical C plasma to be negligible.…”

Section: Methodsmentioning

confidence: 99%

Clinical Validation and Implications of Dried Blood Spot Sampling of Carbamazepine, Valproic Acid and Phenytoin in Patients with Epilepsy

et al. 2014

View full text Add to dashboard Cite

To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 12.6.1.0 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r = 0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT−1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs.

show abstract

“…The RBC partition ratio expressed in drug concentration and quantity can be conveniently converted back and forth with the knowledge of hematocrit (H) according to Eqn. (2), in which V RBC , V PL , and V T stand for the volumes of red blood cells, equilibrating plasma, and the total volume of a whole blood mixture, respectively.…”

Section: Theorymentioning

confidence: 99%

“…2 In a conventional in vitro method, the compound is incubated with whole blood or RBC suspended in plasma, serum or buffer at physiological pH and temperature. In the ex vivo method, the compound is dosed to animals or humans and blood samples are serially taken for analysis using procedures similar to those in the in vitro method.…”

mentioning

confidence: 99%

A novel liquid chromatography/tandem mass spectrometry based depletion method for measuring red blood cell partitioning of pharmaceutical compounds in drug discovery

Yang

et al. 2004

Rapid Comm Mass Spectrometry

View full text Add to dashboard Cite

A novel liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based depletion method for measuring compound partitioning between human plasma and red blood cells (RBC) in a drug discovery environment is presented. Conventionally, RBC partitioning is determined by separate measurements of drug concentrations in equilibrating plasma and whole blood or RBC using separate standards prepared in their respective matrices, i.e., in plasma and whole blood or RBC lysates. The process is very tedious, labor-intensive, and difficult to automate. In addition, interferences from the heme and other highly abundant cellular composites make the measurement of the drug concentration in whole blood or RBC inevitably variable even with a highly specific LC/MS/MS method. Therefore, there is an imminent need to develop a straightforward and fast method to assess the partitioning of drug-like compounds in RBC. This work describes an LC/MS/MS-based depletion assay that measures the compound concentration in plasma that has been equilibrating with RBC. Compounds were spiked into fresh human whole blood and plasma respectively to a final concentration of 500 nM. Both the spiked whole blood and plasma control were incubated at 37 degrees C for up to 60 min. During the time course, aliquots of plasma and whole blood from both incubation mixtures were sampled at 10 and 60 min. The whole blood samples were centrifuged to yield the plasma. The plasma samples from both incubations were extracted using a protein precipitation method, and analyzed using LC/MS/MS under the multiple-reaction monitoring (MRM) mode. The RBC partitioning ratio was calculated using the analyte peak area responses of the plasma samples through an equation deduced in this work. The method was first tested using two commercial compounds, phenoprobamate and acetazolamide, to determine the optimal incubation conditions and the concentration dependency of the assay. The assay reproducibility was also assessed by three inter-day assays for phenoprobamate. This method was further evaluated using 20 commercial compounds of different classes with a wide range of RBC partitioning coefficients and the results were compared with those reported in the literature. Excellent correlation (R2=0.9396) was found between the measured and literature values. In addition, several proprietary compounds were assayed using both the new and traditional methods and the measured partitioning ratios from the two methods are equivalent. The experiments in this work demonstrate that the LC/MS/MS-based depletion method can provide direct and accurate measurement of RBC partitioning for compounds in drug discovery.

show abstract

Distribution of sodium valproate in normal whole blood and in blood from patients with renal or hepatic disease

Cited by 20 publications

References 22 publications

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

Clinical Validation and Implications of Dried Blood Spot Sampling of Carbamazepine, Valproic Acid and Phenytoin in Patients with Epilepsy

A novel liquid chromatography/tandem mass spectrometry based depletion method for measuring red blood cell partitioning of pharmaceutical compounds in drug discovery

Contact Info

Product

Resources

About