Determination of oxcarbazepine in human plasma by high-performance liquid chromatography

Menge, G. P.; Dubois, J.P.

doi:10.1016/s0378-4347(00)84360-1

Cited by 38 publications

(19 citation statements)

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“…The dose of MHD was chosen taking safety and analytical aspects into consideration. The dose of MHD had to be as high as possible, because of the slightly lower sensitivity of the enantioselective (Flesch et al, 1992) compared with the original method for measuring total MHD (Menge and Dubois, 1983).…”

Section: Methodsmentioning

confidence: 99%

“…The weight of each fraction was recorded, and a 20-ml aliquot was retained and kept frozen at Ϫ20°C for determination of OXC, MHD, DHD, (S)-MHD, and of (R)-MHD before and after enzymatic hydrolysis. Plasma and urine concentrations of OXC, MHD, DHD, (S)-MHD, and (R)-MHD were measured by means of a nonenantioselective and an enantioselective high-performance liquid chromatography method (Menge and Dubois, 1983;Flesch et al, 1992). To determine the urinary concentrations of glucuronide of the R enantiomer of MHD …”

Section: Methodsmentioning

confidence: 99%

“…Oxcarbazepine is rapidly reduced by cytosolic arylketone reductases to the monohydroxy derivative (MHD) (Fig. 1) (Schütz et al, 1986;Menge and Dubois, 1983). In humans, formation of MHD is stereoselective, with the two enantiomers formed in a ratio of 80% (S enantiomer of MHD [(S)-MHD]) to 20% (R enantiomer of MHD [(R)-MHD]) (Flesch et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of the Monohydroxy Derivative of Oxcarbazepine and Its Enantiomers after a Single Intravenous Dose Given as Racemate Compared with a Single Oral Dose of Oxcarbazepine

Flesch

Czendlik²,

Renard³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Oxcarbazepine (OXC) is an antiepileptic drug. In humans, OXC is metabolized via reduction and conjugation. Monohydroxy derivative of OXC (MHD) is the major pharmacologically active component after OXC ingestion. This study was performed to characterize the disposition of the two enantiomers of MHD after oral and intravenous administration and to estimate the bioavailability of MHD after a single oral dose administration of OXC compared to a single intravenous administration of MHD. The study was performed in two parts. In a first pilot study, three intravenous doses were given in an ascending manner (150, 200, and 250 mg of MHD; one subject per dose level) to assess the safety, tolerability, and basic pharmacokinetics. Part two was an open, single-center, randomized, two-way crossover, single-dose trial in 12 healthy adult subjects (n ‫؍‬ 6 males and n ‫؍‬ 6 females) given OXC orally (one film-coated 300-mg tablet of OXC) and MHD intravenously (250 mg infused over 30 min). Concentrations of OXC and its metabolites were measured by means of high-performance liquid chromatography methods. OXC given as a tablet is completely absorbed in man under fasting conditions. When MHD is given intravenously, (S)-MHD predominates as free compound in plasma. When OXC is administered orally, the ratio of the area-under-the-curve values of (S)-MHD over (R)-MHD equals 3.8, indicating an enantioselective reduction of the prochiral carbonyl group of OXC.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of the Monohydroxy Derivative of Oxcarbazepine and Its Enantiomers after a Single Intravenous Dose Given as Racemate Compared with a Single Oral Dose of Oxcarbazepine

Flesch

Czendlik²,

Renard³

et al. 2011

Drug Metab Dispos

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“…HPLC techniques are available to quantify OXC and the active metabolite MHD (13). Although the therapeutic range of MHD is not established, clinical experience suggests a target plasma range of 50-125 FrnolL.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Oxcarbazepine

Tecoma

1999

Epilepsia

122

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Summary:The success of carbamazepine (,CBZ) as a broadspectrum antiepileptic drug (AED) has led to its use as first-line therapy in children and adults for partial and generalized tonicclonic seizures. The limitations of CBZ include toxicity in sensitive individuals, autoinduction, which requires dose adjustment when therapy is initiated, and chronic hepatic induction, producing drug interactions when CBZ is used with AEDs and other drugs that undergo hepatic metabolism. One of two main products of CBZ microsomal metabolism, CBZ-I 0,ll -epoxide (formed by oxidation of the double bond between C-10 and C-1 l), appears to provide antiepileptic efficacy but contributes significantly to clinical toxicity. The most common adverse effects of CBZ are central nervous system (CNS) symptoms, followed by gastrointestinal, hepatic, endocrine disturbances, and teratogenic effects. Oxcarbazepine (OXC) was developed to provide a compound chemically similar enough to CBZ to mimic its efficacy and overall safety while improving its side- PHARMACOLOGY ChemistryOxcarbazepine (OXC, 10,11 -dihydro-10-0x0-carbamazepine) is a keto analogue of carbamazepine (CBZ). Like CBZ, it has a dibenzazepine nucleus bearing the 5-carboxamide substituent but is structurally different in the 10,11-position (Fig. 1). OXC is a neutral lipophilic compound with very low aqueous solubility. In humans, OXC is almost immediately converted to the main active metabolite, a 10-monohydroxy derivative, 10,ll ,dihydro-lO-hydroxy-5H-dibenzo( b,flazepine-5-carboxamide (MHD). Mechanism of actionBecause OXC is similar to CBZ in chemical structure and efficacy in animal models, the pharmacologic mechanisms of action may be similar. Inhibition of sustained, high-frequency, repetitive firing of voltagesensitive sodium action potentials has been investigated using intracellular recordings of spinal cord neurons in cell culture. Both MHD and OXC (EC,, = 2-5 x M, respectively) limited repetitive neuronal firing elicited by intracellularly applied depolarizing currents at stable membrane potentials (Em -49 to -55 mV) (1-3). These effects were seen at concentrations much lower than plasma concentrations in patients treated with OXC. Furthermore, the limitation of repetitive firing was found to be frequency-dependent. The V,,, of the neuronal action potentials decreased with successive firing rates, and the percent of stimuli that elicited action potentials decreased significantly as the frequency was increased from 1 to 100 Hz in the presence of M OXC or MHD. These results suggest that blockade of voltagesensitive sodium channels could contribute to the antiepileptic efficacy of OXC and MHD.Blockade of penicillin-induced bursts in hippocampal slices has also been investigated as a measure of antiepileptic efficacy through an effect on potassium channels. MHD was shown to reduce the discharge frequency, and the effect was antagonized by co-application of 4-aminopyridine, a potassium channel blocker ( 1).Thus, MHD appears to have an additional effect on the potassium-dependen...

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“…Most of the analytical methods were published for the analysis of OXC in plasma samples by liquid chromatography-mass spectrometry (LC-MS) and high-performance liquid chromatography (HPLC) methods [6][7][8][9][10][11][12][13][14]. Very few HPLC and UV spectrophotometric methods were reported for the estimation of OXC in bulk and formulations [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

RP-HPLC-PDA method development and validation for the estimation of oxcarbazepine in bulk and formulations

Raghavi¹,

Sindhura²,

Prashanthi³

et al. 2013

Acta Chromatographica

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Summary.A simple, precise, rapid, and accurate liquid chromatography-mass spectrometry (LC-MS) compatible reversed phase high-performance liquid chromatography-photodiode array detection (RP-HPLC-PDA) method has been developed and validated for the estimation of oxcarbazepine (OXC) in bulk and tablet formulations. The chromatographic separation was achieved on Phenomenex C 18 column (150 mm × 4.6 mm, 5.0 μm particle size) using the mobile phase comprising methanol-formic acid (0.02% v/v in water) in the ratio of 50:50 (v/v) at a flow rate of 1 mL min −1 , and OXC was eluted at 6.4 min. Quantification and linearity were achieved at 229 nm over the concentration range of 10-50 μg mL −1 , and the mean percentage of assay was found to be 100.03. The method was validated for specificity, linearity, accuracy, precision, limit of detection (LOD), limit of quantification (LOQ), stability, and robustness as per the International Conference on Harmonisation (ICH) guidelines and it is suitable to be employed in quality control.

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Determination of oxcarbazepine in human plasma by high-performance liquid chromatography

Cited by 38 publications

References 0 publications

Pharmacokinetics of the Monohydroxy Derivative of Oxcarbazepine and Its Enantiomers after a Single Intravenous Dose Given as Racemate Compared with a Single Oral Dose of Oxcarbazepine

Pharmacokinetics of the Monohydroxy Derivative of Oxcarbazepine and Its Enantiomers after a Single Intravenous Dose Given as Racemate Compared with a Single Oral Dose of Oxcarbazepine

Oxcarbazepine

RP-HPLC-PDA method development and validation for the estimation of oxcarbazepine in bulk and formulations

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