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Volume 16, Issue 1


Volume 13 (2015)

A new selective, and sensitive method for the determination of lixivaptan, a vasopressin 2 (V2)-receptor antagonist, in mouse plasma and its application in a pharmacokinetic study

Haitham Alrabiah
  • Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh, 11451, Saudi Arabia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Mohammed Abunassif
  • Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh, 11451, Saudi Arabia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sabry Attia
  • Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh, 11451, Saudi Arabia
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/ Gamal Abdel-Hafiz Mostafa
  • Corresponding author
  • Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh, 11451, Saudi Arabia
  • Microanalytical Lab., Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, Egypt
  • Email
  • Other articles by this author:
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Published Online: 2018-07-18 | DOI: https://doi.org/10.1515/chem-2018-0063


A new, selective and sensitive HPLC method for the determination of lixivaptan, an oral selective vasopressin 2 (V2)-receptor antagonist, was investigated and validated. A Waters symmetry C18 column was used as a stationary phase in isocratic elution mode using a mobile phase composed of KH2PO4 (100 mM)-acetonitrile (40: 60, v/v) at a flow rate of 1.5 mL min-1. Diclofenac was used as the internal standard (IS). Lixivaptan and the IS were extracted from plasma by protein precipitation and were detected at 260 nm. Lixivaptan and diclofenac were eluted at 3.6 and 6.2 min, respectively. The developed method showed good linearity over the calibration range of 50 -1000 ng mL-1 with a lower limit of detection of 16.5 ng mL-1. The extraction percentage of lixivaptan in the mouse plasma was in the range of 88.88 - 114.43%, which indicates acceptable extraction. The aforementioned method was validated according to guidelines of the International Council on Harmonization (ICH). The intra- and inter-day coefficients of variation did not exceed 5.5%. This method was presented to be simple, sensitive, and accurate and was successfully adapted in a pharmacokinetic study of the profile of lixivaptan in mouse plasma. A mean maximum plasma concentration of lixivaptan of 113.82 ng mL-1 was achieved in 0.5 h after oral administration of a 10 mg kg-1 dose in mouse as determined using the developed method.

Keywords: Lixivaptan; HPLC/UV; mouse plasma; pharmacokinetic

1 Introduction

Lixivaptan (LIX) is an orally-administered pharmacological compound used as an antagonist of vasopressin, a hormone that is associated with heart failure [1, 2] and has a role in maintaining water balance in the body. Lixivaptan functions by blocking the vasopressin 2 (V2) receptor and can potentially be used for the treatment of hyponatremia [3,4,5]. Hyponatremia is the condition in which the concentration of sodium in the blood is lower than normal. Lixivaptan can eliminate excess fluids from the body and keep blood sodium levels within the normal range. It is a selective nonpeptide V2 antagonist [3, 4] and a chemical derivative of benzodiazepine, with the chemical name 5-fluoro- 2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin- 10(11H)-ylcarbonyl)-3 chlorophenyl]benzamide (Figure 1) [6]. Lixivaptan strongly binds to V2 receptors in the kidneys, preventing the insertion of aquaporin channels into the apical membrane layer, thus resulting in an increase in solute-free water excretion and sodium retention [7].

Chemical structure of: (A) lixivaptan and (B) the internal standard (IS) diclofenac (DC).
Figure 1

Chemical structure of: (A) lixivaptan and (B) the internal standard (IS) diclofenac (DC).

Several studies were directed toward assessing the pharmacodynamics and pharmacokinetics of lixivaptan [8,9,10,11]. Lixivaptan is absorbed quickly with a mean estimated Tmax of < 1 h. A crosswise analysis showed that the rate of clearance, volume of distribution, and half-life of lixivaptan were in a correlation between the LIX concentration with free water clearance [10]. The pharmacokinetic study need to highly sensitive technique to determine LIX in lower concentration as well as their detection in plasma metrics without interferences. Therefor this study aimed to develop an HPLC for determination of LIX in mice plasma and its application to pharmacokinetic study.

Validation of any developed method is essential in order to prove that the method is acceptable for the proposed use. The proposed method should also satisfy criteria related to estimating the drug in biological fluids or various matrices (biological samples) as well as in clinical studies [12,13,14]. We therefore developed a new HPLC method to which international standards, such as the guidelines of US Food and Drug Administration (FDA) [15] and the International Council for Harmonization (ICH) [16], were accordingly applied for validation.

The rationale for choosing HPLC is based on the advantages of this technique, including its simplicity, sensitivity and accuracy, which have made it commonly used for drug analysis in many laboratories [17,18,19]. The proposed HPLC method involves detection via ultraviolet spectroscopy, and it was optimized according to the selected validation criteria [15, 16]. This work represents a complementary study to our initial work, which was based on HPLC-MS/MS analysis [20].

In the present investigation, a sensitive, selective, and accurate HPLC-UV method is proposed for the assay of lixivaptan in mouse plasma. A protein precipitation procedure as an extraction method was used for extracting lixivaptan from mouse plasma. The validation parameters of lixivaptan determination as a bioanalytical method were optimized according to ICH guidelines. The suggested method was successfully applied in a pharmacokinetic study of lixivaptan in mouse plasma.

2 Materials and Methods

2.1 Reagents and materials

Lixivaptan and diclofenac sodium (DC) (Figure 1) of purity > 99% (Sigma-Aldrich, Steinheim, Germany) were used as references in this study. HPLC-grade acetonitrile and methanol were purchased from Zeus Quimica S.A (Barcelona, Spain). Analytical grade “potassium dihydrogen phosphate, phosphoric acid, perchloric acid and trifluoroacetic acid were acquired from AVONCHEM (Macclesfield, Cheshire, England). Double distilled water was produced using a cartridge system (Waters Millipore, Milford, USA)”. Naltrexone hydrochloride, cyclobenzaprine hydrochloride, clonidine hydrochloride, tizanidine hydrochloride, pravastatin sodium, fenofibrate, fenofibric acid, phenobarbital sodium, and 7-Methyl- 6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine (LE 300) were purchased from Sigma (St. Louis, Mo, USA).

2.2 Apparatus and chromatographic conditions

“The HPLC analysis was carried out using a Waters HPLC system (Milford, USA) equipped with 1500 series HPLC pump”, operated at a flow rate of 1.5 mL min-1. A dualwavelength “ultraviolet detector (2489) and an autosampler (717plus)” were used. Data were collected with an “Empower pro Chromatography Manager for data acquisition and analysis”.

Chromatographic separations were completed using an analytical Waters Symmetry “C18 analytical column (125 mm ´ 4.6 mm i.d. ´ 3 μm particle size (Waters, USA) coupled with a Symmetry C18 sentry guard column (20 mm)”. All solutions were degassed by “ultra-sonication and filtered through a 0.45 μm filter (Millipore)”.

The mobile phase consisted of KH2PO4 (100 mM) and acetonitrile (40: 60, v/v). All separations were achieved in isocratic mode at a flow rate of 1.5 mL min-1 at 25°C. The injection volume was 50μL and the absorbance of eluents was recorded at 260 nm.

2.3 Preparation of solutions and plasma samples

Stock solutions of lixivaptan and DC were prepared by dissolving a quantity of the drug and standard in acetonitrile and methanol, respectively, to yield a concentration of 1 mg mL.1 Three working solutions of LIX (100 and 10 and 1 μg mL-1 ) and two working solution of DC (100 and 10 μg mL-1) were prepared by suitable dilution. All solutions were stored at 4°C.

Mouse plasma (100 μL) was spiked with a suitable amount of lixivaptan ( 10 and 1 μg mL-1) and DC (10 μg mL-1) to give a final concentration of 50, 100, 200, 400, 800, and 1000 ng mL-1 lixivaptan and 2 μg mL-1 DC, with each sample being prepared in a 2.0 mL disposable polypropylene micro-centrifuge tube. Then, 500 μL acetonitrile was added to induce protein precipitation, and each tube was vortexed for about 1 min. The samples were then centrifuged at 10,000 rpm at room temperature (25°C) for 9 min. The upper layer solution was filtered through a simple pure filter (0.22 μm) and the clarified sample was injected into the HPLC system. Analysis of each lixivaptan concentration was repeated six times. The average peak area ratio for each sample was estimated and plotted against LIX concentration. Blank mouse plasma samples were prepared in the same way using the diluting solvent instead of lixivaptan and DC.

2.4 Bioanalytical method of validation

The linearity of the method was evaluated according to ICH guidelines [16]. A calibration graph was obtained by plotting the area ratios of lixivaptan to DC (IS) against the initial lixivaptan concentration. The equation of the calibration curve was obtained using the fitting of the plot. Calibration plots for lixivaptan were prepared using six concentration points (50, 100, 200, 400, 800, and 1000 ng mL-1). Each concentration point was repeated six times, and the average value was calculated and used to plot the calibration graph.

The accuracy of the determination of lixivaptan was assessed explicitly by spiking known concentrations of lixivaptan into mouse plasma. The % recovery was calculated using the following formula: ([peak area ratio of extract/mean peak area ratio of un-extracted drug] ´100).

The intra-day and inter-day precisions of the lixivaptan assay were calculated by the repeatability of the analysis of three quality control samples (75, 300 and 700 ng mL-1) within the same day or in three different days, respectively. The accuracy and precision of the established method for lixivaptan were determined according to ICH guidelines for bio-analytical method validation [16].

The stability of lixivaptan in mouse plasma was evaluated using three replicate samples of QC concentrations (75, 300, and 750 ng mL-1). The stability conditions were: at 25°C (room temperature) for 8 h, at - 4°C for one week, and in the auto-sampler tray for 12 h. Calculation of accuracy and precision of the quality control samples was carried out using a calibration curve based on fresh mouse plasma.

2.5 Pharmacokinetic Application

2.5.1 Animal maintenance

Adult male white” Swiss albino mice” weighing 25-30 g (10 - 12 weeks old) were obtained from the “Experimental Animal Care Center, King Saud University”. The animals were maintained in an “air-conditioned animal house at a temperature of 25-28°C, relative humidity of 50%, and 12:12h light and dark photo-cycle”. The animals were provided with standard diet pellets and water ad libitum.The experiments were approved by the “Ethics Committee of the Experimental Animal Care Society, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.”

2.5.2 Pharmacokinetic study

After two days of housing, the mice were randomly divided into eight groups (six mice each), then seven of the groups were orally administered with 10 mg kg-1 of lixivaptan, and the remaining group was administered “dimethyl sulfoxide in saline to serve as blank mouse plasma” [21]. The injection volume of the drug was 0.01 mL g-1 body weight. Lixivaptan was administered at 0.5, 1, 1.5, 2, 3, 4, and 8h before blood sampling. Each time point was repeated six times with different mice. The blood samples were withdrawn from the heart (1.0 mL). The plasma samples were separated from the serum by centrifugation at 4000 rpm for 5 min, and then preserved at -20°C until analysis.

3 Results and discussion

This study describes an HPLC-UV method for the assay of lixivaptan. To select an internal standard (IS), we tested different drugs with similar chemical structures or pKa values to the drug, including naltrexone, cyclobenzaprine, clonidine, tizanidine, pravastatin, fenofibrate, fenofibric acid, LE 300, and phenobarbital sodium. Most of the tested drugs failed because they had short elution times (less than 1 min), because they interfered with lixivaptan, or because an excessively large separation was obtained. DC was selected as the IS for the quantification of lixivaptan because it was separated at a suitable elution time of approximately 3.6 min under optimal chromatographic separation conditions.

Suitable chromatographic conditions were studied and optimized through multiple trials to achieve good resolution and a symmetric peak shape for lixivaptan and DC, as well as a suitable elution time. For the optimization of the mobile phase composition, different mobile phase components, such as methanol, water and acetonitrile in different ratios, were tested. Acetonitrile: KH2PO4 showed better separation than methanol: KH2PO4; however, the resolution was still not complete, and approximately 1.2 (about 90%) resolution was obtained. Another trial involved the use of KH2PO4 of different ionic strengths (25, 50, and 100 mM), and 100 mM appeared to be the most suitable ionic strength to obtain satisfactory resolution.

The absorbance spectrum of lixivaptan showed two maxima, at 210 and 260 nm. The peak at 260 nm resulted in acceptable selectivity when compared with that at 210 nm. In addition, at 210 nm, the blank showed a higher absorbance intensity compared with that at 260 nm. Therefore, the optimal conditions of chromatographic separation were found to be a mobile phase consisting of acetonitrile:100 mM KH2PO4, 60:40 (v/v) and detection at wavelength 260 nm. Under these conditions, lixivaptan analysis demonstrated a good capacity factor, separation factor, resolution, and peak symmetry.

3.1 Extraction procedure

A clean-up procedure is often essential to remove plasma proteins prior to analysis. The extraction step in general involves time-consuming and laborious sample pretreatments, which often include the use of liquid or solid phase extraction. A solvent-based protein precipitation method was developed using different solvents such as perchloric acid, trifluoroacetic acid and acetonitrile. The optimal solvent was acetonitrile, which resulted in a good recovery (see Table 1). The extraction recovery of lixivaptan from mouse plasma was in the range of 88.88-114.43%, which is consistent with published standards [12].

Table 1

Extraction % recovery of lixivaptan from spiked mouse plasma using solvent deproteinization procedure.

3.2 Specificity

To investigate the specificity of the new method, a variety of blank mouse plasma samples were examined individually to detect any potential interference. Chromatograms of mouse blank plasma and mouse plasma spiked with 2 μg mL-1 DC and 200 ng mL-1 lixivaptan are presented in Figure 2. The peaks of lixivaptan and DC were well resolved at the correct retention times of 6.2 and 3.6 min, respectively. In mouse plasma, no peaks similar to either lixivaptan or DC were observed over the elution time of both the drug and the IS. The analysis was completed within 10 min with complete separation. The protein precipitation procedure of the plasma samples was appropriate for the separation and extraction of the drug from the plasma in the absence of any interference from similar peaks (Figure 3). The system suitability parameters for lixivaptan are listed in Table 2 based on isocratic elution of the drug at a flow rate of 1.5 mL min-1 and a detection wavelength of 260 nm.

HPLC chromatogram of the analysis of lixivaptan in drug-free plasma: (A) blank plasma, (B) mouse plasma spiked with 200 ng mL-1 and 2 μg mL-1 of lixivaptan and DC, respectively.
Figure 2

HPLC chromatogram of the analysis of lixivaptan in drug-free plasma: (A) blank plasma, (B) mouse plasma spiked with 200 ng mL-1 and 2 μg mL-1 of lixivaptan and DC, respectively.

HPLC chromatograms of mouse plasma (A) at zero time (Blank) and (B) 0.5 h after injection.
Figure 3

HPLC chromatograms of mouse plasma (A) at zero time (Blank) and (B) 0.5 h after injection.

Table 2

Chromatographic system suitability parameters.

3.3 Validation of the Method

3.3.1 Linearity and sensitivity

The investigated method showed good linearity for lixivaptan over the calibration range of 50-1000 ng mL-1 lixivaptan. The regression correlation coefficient was r2 = 0.9989. The calibration curve equation was y = 0.001x- 0.0127. The good linearity of the calibration graph is indicated by the high value of the correlation coefficient and the standard deviation parameters of the obtained calibration curve [22]. Table 3 gives an outline of the general analytical characterization of the investigated method. The lower limit of quantification and lower limit of detection of lixivaptan in mouse plasma was estimated at 50.0 and 16.5 ng mL,-1 respectively (signal-to-noise ratio of 10 or 3)

Table 3

Analytical parameters of the investigated HPLC method

3.3.2 Accuracy and precision

The accuracy and precision of the studied method were evaluated by assaying different concentrations plotted in the calibration curve, encompassing a broad range of concentrations (75, 300 and 700 ng mL-1) of lixivaptan. The precision of the method was estimated in terms of injection repeatability, analysis repeatability during a single day, and intermediate precision over multiple days. The accuracy and precision of the investigated method were within an adequate range as defined by ICH guidelines [16]. The intra-day accuracy and precision were within the range 95.0-97.77% and 0.94 - 4.63%, respectively. The interday accuracy ranges were 91.0-92.3% and 0.97 - 4.66%, respectively (Table 4).

Table 4

Intra- and inter-day accuracy and precision of lixivaptan quality control samples determined for the investigated HPLC method.

3.3.3 Stability

Drug stability was assessed under standard conditions. The concentrations calculated following the trials varied only within ±10%. During optimization, sample processing, or bench study, no degradation of lixivaptan was observed (Table 5). In addition, no loss of lixivaptan concentration was recorded for a relatively short period of time or during refrigeration. The newly developed procedure for the assay of lixivaptan can be performed under ordinary research facility conditions with a high degree of reproducibility without any recorded loss.

Table 5

Stability of lixivaptan in mouse plasma based on the proposed HPLC method.

3.4 Pharmacokinetic Study

The investigated method was used to perform a preliminary pharmacokinetic study of lixivaptan in mouse plasma. The concentrations of lixivaptan in plasma samples at different time points after dosing were assessed individually. A plasma concentration time curve (AUC) of lixivaptan was plotted (Figure 4) using the lixivaptan concentration determined at each time point. Lixivaptan pharmacokinetic parameters were estimated from the concentration time curve. After oral administration of 10 mg Kg-1 lixivaptan, the mean values of the pharmacokinetic parameters Tmax and Cmax were determined to be 0.5 h and 113.82±28.1 ng mL-1, respectively. Determination of these parameters represents a demonstration of the utility of the developed method in pharmacokinetic research.

Concentration-time curve of lixivaptan in mouse plasma after oral administration of 10 mg kg-1 lixivaptan. Each point represents mean value ± SD.
Figure 4

Concentration-time curve of lixivaptan in mouse plasma after oral administration of 10 mg kg-1 lixivaptan. Each point represents mean value ± SD.

4 Conclusion

In the current study, we investigated, for the earliest time, a simple, sensitive, and selective method for the determination of lixivaptan in mouse plasma samples using HPLC separation and UV detection. Acetonitrile was used as protein precipitation solvent for extracting lixivaptan from mouse plasma, and the method was validated using ICH guidelines. The method proved to be of acceptable accuracy, precision, recovery, selectivity, and sensitivity. The assay was further applied in a pharmacokinetic study of lixivaptan in mouse plasma, which shows the applicability of the method for use in clinical studies.


The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through research group project no. RGP-1436-024.


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About the article

Received: 2017-09-19

Accepted: 2018-04-09

Published Online: 2018-07-18

Conflict of interest: The authors declare no conflict of interest.

Citation Information: Open Chemistry, Volume 16, Issue 1, Pages 614–620, ISSN (Online) 2391-5420, DOI: https://doi.org/10.1515/chem-2018-0063.

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© 2018 Haitham Alrabiah et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. BY-NC-ND 4.0

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