Journal of Pharmaceutical and Biomedical Analysis 100 (2014) 294–299

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Simultaneous determination of clevidipine and its primary metabolite in dog plasma by liquid chromatography–tandem mass spectrometry: Application to pharmacokinetic study Ying Zhou, Huqun Li, Xiaomeng He, Mengmeng Jia, Yang Ni, Mingzhen Xu, Hui Chen ∗ , Weiyong Li ∗ Institute of Clinic Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

a r t i c l e

i n f o

Article history: Received 18 June 2014 Received in revised form 6 August 2014 Accepted 8 August 2014 Available online 17 August 2014 Keywords: Clevidipine Metabolite Liquid chromatography tandem mass spectrometry Pharmacokinetic

a b s t r a c t A simple and rapid liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous determination of clevidipine and its primary metabolite H152/81 in dog plasma after protein precipitation with acetonitrile using felodipine as the internal standard (IS). Chromatographic separation was performed on a XB C18 column (2.1 mm × 50 mm, 3.5 ␮m) under isocratic conditions with the mobile phase consisting of acetonitrile and 20 mM ammonium acetate buffer (pH 7.0) (40:60, v/v) at the flow rate of 0.3 ml/min. The run time was 5.5 min. Mass spectrometric analysis was performed on a triple quadrupole mass spectrometer operated in the multiple reaction monitoring (MRM) mode with the transitions of m/z 473.0→338.2 for clevidipine, m/z 356.1→324.0 for H152/81 and m/z 383.9→338.2 for the IS. The method was fully validated in terms of selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, stability, matrix effect and recovery over a concentration range of 0.15–200 ng/ml for clevidipine and 10–2000 ng/ml for H152/81, respectively. The analytical method was applied to support a pharmacokinetic study of simultaneous determination of clevidipine and H152/81 in ten healthy beagle dogs. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Chronic hypertension is often controlled by oral antihypertensive drugs [1]. However, subjects with acute, severe hypertension or in the case of cardiac surgery require intravenous therapy when rapid, controlled blood pressure reduction is necessary and the administration of oral agents is not feasible [2–4]. Clevidipine is an ultrashort-acting, third-generation intravenous calcium channel blocker, which lowers blood pressure through arterial-specific peripheral vasodilation without adverse myocardial effects [5–7]. Owing to its vascular selectivity and rapid onset and offset of antihypertensive action [7,8], clevidipine is used for short-term intravenous control of blood pressure [2]. Clevidipine is rapidly metabolized by esterases in blood and extravascular tissues to its primary metabolite H152/81 [2], resulting in an initial half-life of approximately 1 min [9]. Recent studies have found that both clevidipine and H152/81 can induce or inhibit CYP3A4 [10],

∗ Corresponding authors. Tel.: +86 27 85726063; fax: +86 27 85727851. E-mail addresses: shining [email protected] (H. Chen), wenzhang [email protected] (W. Li). http://dx.doi.org/10.1016/j.jpba.2014.08.018 0731-7085/© 2014 Elsevier B.V. All rights reserved.

hence there is a need to determine both the parent drug clevidipine and its primary metabolite H152/81, especially in combination therapy, which is very common in subjects with cardiovascular disease or in the case of cardiac surgery. The determination of clevidipine or H152/81 levels individually has been previously performed through HPLC methods with UV [11,12] or fluorescence detection [13,14]. Gas chromatography (GC) with electron-capture detection (ECD) [15] or mass spectrometry (MS) [13] is also an alternative for the determination of clevidipine. Liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method has been only mentioned slightly in one article [5] on the pharmacokinetics, pharmacodynamics, and safety of clevidipine. However, the specific method was not reported. In this paper, we first report a highly selective and sensitive LC–MS/MS method for the determination of clevidipine and H152/81 in dog plasma. It is expected that this method would be efficient in analyzing a large number of plasma samples obtained for pharmacokinetic, bioavailability or bioequivalence studies of clevidipine and its primary metabolite H152/81. This new method has been fully validated in terms of selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, stability, matrix effect and recovery. It has been successfully applied

Y. Zhou et al. / Journal of Pharmaceutical and Biomedical Analysis 100 (2014) 294–299

in a pharmacokinetic study of clevidipine and H152/81 in ten healthy Beagle dogs.

2. Material and methods 2.1. Chemicals and reagents Clevidipine (99.60% purity), the primary metabolite of clevidipine H152/81 (99.26% purity) and felodipine (internal standard, IS, 99.14% purity) were generously supplied by Wuhan Wuyao Pharmaceutical Co., Ltd. (Wuhan, China). Methanol and acetonitrile of HPLC grade were purchased from Merck KGaA (Darmstadt, Germany). Analytical grade formic acid and ammonium acetate were purchased from Dima Technology Inc. (Guangzhou, China). Ultrapure water (Chengdu Ultra Technology Co., Ltd., Chengdu, China) was used throughout the study. Blank dog plasma was provided by Union Hospital, Tongji Medical College, Huazhong University of Science & Technology.

2.2. Instrumentation and conditions 2.2.1. Liquid chromatography An Agilent 1200 liquid chromatography system (Agilent Technologies, Santa Clara, CA, USA) equipped with a quaternary pump, a degasser, an autosampler and a column oven was used. Chromatographic separation was achieved on an Ultimate XB-C18 column (2.1 mm × 50 mm, 3.5 ␮m, Welch Materials, Inc., Shanghai, China) using a mobile phase consisting of acetonitrile and 20 mM ammonium acetate (pH 7.0) (40:60, v/v) at a flow rate of 0.3 ml/min with isocratic elution. The autosampler was conditioned at +4 ◦ C and the column oven was conditioned at +30 ◦ C. The injection volume was 5 ␮l.

2.2.2. Mass spectrometry The HPLC system was coupled with an API 4000 triple quadrupole mass spectrometer (AB Sciex, Framingham, MA, USA) equipped with an ESI Turbo ionspray. The mass spectrometer was operated in positive ion mode with the capillary voltage and source temperature set at 5500 V and 500 ◦ C, respectively. Collision activated dissociation gas (CAD) was set at 8, the curtain gas (CUR) at 25 and nebulizer and heater gas (GS1 and GS2) were fixed, respectively, at 30 and 50. Quantification was performed using multiple reaction monitoring (MRM) mode of the transitions of m/z 473.0→338.2 for clevidipine, m/z 356.1→324.0 for H152/81 and m/z 383.9→338.2 for the IS with scan time of 200 ms per transition. Data were acquired and processed using Analyst 1.5.1 software (AB Sciex, Framingham, MA, USA).

2.3. Preparation of standard solution The appropriate amount of clevidipine and H152/81 was exactly weighed and dissolved in methanol to prepare stock standard solution at a concentration of 210.4 and 222.3 ␮g/ml, respectively. A series of combined standard working solutions were freshly prepared by diluting the stock standard solution with methanol at concentrations of 1.5, 5, 20, 100, 500, 1000 and 2000 ng/ml for clevidipine, and 100, 200, 500, 1000, 2000, 5000, 10,000 and 20,000 ng/ml for H152/81, respectively. The IS solution was prepared by dissolving felodipine in methanol to 3 ␮g/ml. For the validation of the method, three concentration levels of standard solution of clevidipine (4.5, 500 and 1600 ng/ml) and H152/81 (300, 5000 and 16,000 ng/ml) were used to prepare QC plasma samples.

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2.4. Sample processing 0.2 ml of plasma and 20 ␮l of IS (3 ␮g/ml) were added to a 1.5 ml polypropylene tube. Then 0.6 ml of acetonitrile, which was cooled at +4 ◦ C in advance, was added to the tube for precipitation. The sample was vortex-mixed for 30 s, and centrifuged at 12,000 rpm for 5 min under +4 ◦ C. The supernatant (5 ␮l) was injected into the LC–MS/MS system. 2.5. Method validation 2.5.1. Selectivity The selectivity of the method was evaluated by comparing the chromatograms of blank plasma samples from six individual dogs to those of corresponding blank plasma spiked with analytes and IS and the plasma samples from the dogs after intravenous infusion of clevidipine at a dose of 17 ␮g/kg/min. 2.5.2. Linearity and lower limit of quantification (LLOQ) Calibration curves were established by spiking 180 ␮l of blank plasma samples with 20 ␮l of standard working solutions, using seven different concentrations at 0.15, 0.5, 2, 10, 50, 100 and 200 ng/ml for clevidipine, and 10, 20, 50, 100, 200, 500, 1000 and 2000 ng/ml for H152/81, respectively. Calibration curves were constructed by plotting the peak area ratio (y) of each analyte to IS versus nominal concentrations (x) of analytes using a 1/x2 weighted least square linear regression. The LLOQ was defined as the lowest concentration point of the calibration curve at which the relative standard deviation (RSD) was below 20% and the relative error (RE) was within ±20% [20]. RE is defined as: (measured value-nominal value)/nominal value × 100%. 2.5.3. Precision and accuracy The accuracy as well as the intra- and inter-run precision of the method were evaluated by determining QC samples at three concentrations in five replicates on three consecutive days with calibration curves obtained daily. The precision at each QC concentration was expressed as relative standard deviation (RSD) and the accuracy as relative error (RE). The intra-day and inter-day precisions were required to be less than 15%, and the accuracy to be within ±15%. 2.5.4. Extraction recovery and matrix effect The extraction recovery was determined by dividing the peak areas of analytes added into blank plasma and extracted through the same procedure with those obtained from the analytes spiked into equivalent volume of post-extraction supernatant at three concentration levels. The matrix effect was measured by comparing the peak areas obtained from six plasma samples with the analytes spiked after extraction, at three QC concentration levels, with those of standard solutions at the same concentrations. The extraction recovery and matrix effect of IS were also evaluated using the same procedure at a single concentration. 2.5.5. Stability Stabilities of analytes were examined under different storage conditions using five replicates of QC samples at three concentration levels. The short-term temperature stability was assessed by analyzing QC samples that were kept at +4 ◦ C for 2 h. The longterm stability was evaluated by freezing QC samples at −80 ◦ C for 20 days. The autosampler stability was assessed by placing processed QC samples in the autosampler at +4 ◦ C for 24 h, and the freeze–thaw stability was measured after three freeze and thaw cycles from −80 ◦ C to +4 ◦ C.

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2.6. Application to a pharmacokinetic study The method was applied to study the pharmacokinetic profile of clevidipine and its primary metabolite H152/81 in Beagle dogs after a single intravenous infusion administration of clevidipine butyrate at a dose rate of 17 ␮g/kg/min over a period of 40 min. The study abided by the ethics and regulations of animal experiments of the Experimental Animal Center of Huazhong University of Science and Technology, China. Blood samples were collected before and 0, 2, 5, 10, 20, 30, 40, 42, 45, 50, 60, 70, 80, 90 and 120 min post-dosing and centrifuged immediately at 6000 rpm for 3 min at +4 ◦ C to obtain plasma, which was frozen in liquid nitrogen and then stored at −80 ◦ C until analysis. Plasma concentration–time data for clevidipine and H152/81 were analyzed by noncompartmental analysis using the software program WinNonlin® Professional version 6.3 (Pharsight® Corporation, Mountain View, CA, USA). Pharmacokinetic parameters included AUC(0−t) (the area under the plasma concentration versus time curve from time 0 to 120 min), AUC(0−∞) (the area under the plasma concentration versus time curve from time 0 to infinity), Cmax (the maximum peak concentration), Tmax (the time to Cmax ) and t1/2 (elimination half-life). Cmax and Tmax were obtained directly from the curves; AUC(0−t) was calculated according to the trapezoidal method; AUC(0−∞) was calculated by AUC0−t + Ctn /ke, where Ctn was the last sample concentration that can be determined and ke was the terminal elimination rate constant which was obtained though the slope of the linear portion of logarithms of concentration–time curve; t1/2 was calculated with t1/2 = 0.693/ke. 3. Results and discussion 3.1. Conditions for ESI-MS/MS The mass spectrometer was tuned in both positive and negative ionization modes with ESI Turbo ionspray for optimum response of each analyte. Both analytes contain the tert-amino group, but the carboxylic acid group only exists in the structure of H152/81, which made it possible for H152/81 to form the protonated molecular ion of m/z 353.9 in negative ionization mode. It was demonstrated that both of them were easily protonated and generated positive

product ions with higher sensitivity due to the presence of the tertamino group. Therefore, we preferred the positive ion mode for simultaneous determination. In the positive ion mode, clevidipine, H152/81 and IS formed the protonated molecular ions of m/z 473.0, m/z 356.1 and m/z 383.9, respectively, which were chosen as the precursor ions for the analytes. Parameters such as the ESI source temperature, capillary and cone voltage, desolvation temperature and flow rate of desolvation gas as well as the collision energy were optimized to obtain the optimum response of analytes. Finally the ion transition of m/z 473.0→338.2, m/z 356.1→324.0 and m/z 383.9→338.2 was employed for quantification of clevidipine, H152/81 and IS, respectively. 3.2. Conditions for HPLC We tried several different columns to achieve good peak shape and retention of both compounds and found that an ODS column and a XB-C18 column were suitable for the analysis of both analytes, with sharp and symmetrical peak shape. The differences in terms of the intensity of response as well as the length of runtime were as follows: chromatographic separation was performed on the Inertsil® ODS-SP column (2.1 mm × 100 mm, 3 ␮m) with higher response but longer analysis time (about 10 min) due to its column length. On the contrary, it took less time (5.5 min) when chromatographic separation was performed on the XB C18 column (2.1 mm × 50 mm, 3.5 ␮m) in spite of lower response of both analytes, especially for H152/81. Indeed the sensitivity was sufficient for the determination of clevidipine and H152/81 in dog plasma. Therefore, the XB-C18 column was chosen. Regarding the mobile phase, a small amount of formic acid contributed to the formation of [M+H]+ in positive ion mode, resulting in higher response. Each sample was analyzed within 5.5 min under isocratic elution in the present method. 3.3. Sample collection and preparation It has been reported that esterase inhibitors, such as sodium dodecyl sulfate (SDS), bis-nitrophenyl phosphate (BNPP) and NaF, were used in the quantitative analysis of unstable compounds [16,17]. Among those agents, the most commonly used esterase

Fig. 1. Chromatograms and retention times of analytes: (A) blank plasma; (B) blank plasma spiked at the LLOQ with clevidipine (0.15 ng/ml), H152/81 (10 ng/ml) and IS (300 ng/ml); (C) plasma sample obtained 60 min after intravenous infusion of clevidipine.

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Table 1 Intra- and inter-day precision and accuracy of QC samples in plasma. Nominal concentration (ng/ml)

Intra-day (n = 5) mean ± SD

RSD (%)

RE (%)

Inter-day (n = 5) mean ± SD

RSD (%)

RE (%)

Clevidipine 0.45 50 160

0.455 ± 0.0424 49.3 ± 2.78 159 ± 8.26

9.33 5.64 5.20

1.07 −1.44 −0.75

0.446 ± 0.0442 50.1 ± 2.61 156 ± 7.67

9.90 5.22 4.91

−0.79 0.13 −2.33

H152/81 30 500 1600

31.7 ± 2.15 518 ± 21.6 1540 ± 66.7

6.80 4.16 4.33

5.60 3.68 −3.75

30.6 ± 2.53 502 ± 24.9 1554 ± 60.1

8.29 4.96 3.87

1.91 0.32 −2.88

RE (%) = (measured value-nominal value)/nominal value × 100%. Table 2 Results of extraction recovery and matrix effect of clevidipine and H152/81 in plasma (n = 5). Analyte

Nominal concentration (ng/ml)

Recovery

0.45 50 160

Clevidipine

30 500 1600

H152/81

Matrix effects

Mean (%)

RSD (%)

Mean (%)

RSD (%)

88.9 91.2 92.7

7.25 5.01 4.68

94.3 98.4 97.6

4.64 3.32 2.87

93.2 95.6 94.4

6.52 5.43 4.65

89.5 91.3 93.5

5.63 3.56 2.31

inhibitor was SDS, which was more efficient in preventing hydrolysis [16] and used in the determination of clevidipine in whole blood [2,13]. It was also proved in our study that clevidipine was unstable in whole blood and SDS could prevent clevidipine from hydrolysis obviously (data not shown). However, clevidipine was found to be relevantly stable for at least 2 h in dog plasma with or without SDS, especially at a low temperature. That is probably because esterases mainly exist in erythrocyte. Besides, esterases in dogs may be different from humans. Taking all above into consideration, we decided to collect dog plasma, instead of whole blood, for the assay of clevidipine and H152/81. In order to minimize the hydrolysis of clevidipine during sample collection, the whole blood was centrifuged immediately at +4 ◦ C to obtain plasma, which was transferred to 1.5 ml Eppendorf tubes and immediately frozen in liquid nitrogen. In addition, the process of sample preparation for LC–MS/MS analysis should be at a reduced temperature (+4 ◦ C) [18] to avoid the hydrolysis of clevidipine by the small amount of esterases remaining in plasma. 3.4. Method validation 3.4.1. Selectivity and specificity Selectivity was assessed by comparing the chromatograms of blank dog plasma from six different sources with the corresponding

spiked plasma. As shown in Fig. 1, the retention times of clevidipine, H152/81 and IS were 4.51 min, 1.06 min and 3.82 min, respectively. No interference and a low background noise were found, which indicated that the method exhibited good specificity and selectivity.

3.4.2. Linearity and LLOQ The calibration curves of analytes were linear within the concentrations ranging from 0.15 to 200 ng/ml for clevidipine and 10 to 2000 ng/ml for H152/81. The weighing coefficient was 1/x2 and the mean correlation coefficient of both was >0.9966. The LLOQ of clevidipine and H152/81 was 0.15 ng/ml and 10 ng/ml, respectively, which were sufficient for the determination of the analytical samples, and also lower than those reported before [5,19].

3.4.3. Assay precision and accuracy The details of the intra- and inter-day precision and accuracy for both analytes are shown in Table 1. The results were within the acceptable range required to meet current guidelines for bioanalytical methods [20], which indicated that the method was precise and accurate.

Table 3 Stability results of clevidipine and H152/81 in plasma under different conditions (n = 5). Analyte

Clevidipine

H152/81

Nominal concentration (ng/ml)

0.45 50 160 30 500 1600

Long-term

Short-term Actual concentration (ng/ml) 0.47 ± 0.04 50.36 ± 1.78 161.00 ± 3.39 30.48 ± 2.34 504.80 ± 20.22 1594.00 ± 55.95

Short-term: +4 ◦ C for 2 h. Long-term: −80 ◦ C for 20 days. Freeze–thaw: three freeze and thaw cycles from −80 ◦ C to +4 ◦ C. Extract-left: +4 ◦ C for 24 h.

RE (%)

4.44 0.72 0.63 1.60 0.96 −0.38

Actual concentration (ng/ml)

Freeze–thaw RE (%)

Actual concentration (ng/ml)

Extract-left RE (%)

Actual concentration (ng/ml)

0.46 ± 0.05 49.28 ± 2.78 157.60 ± 6.15

2.84 −1.44 −1.50

0.44 ± 0.02 49.36 ± 1.38 163.00 ± 2.74

−2.13 −1.28 1.88

0.49 ± 0.04 51.64 ± 2.60 162.40 ± 5.59

31.06 ± 2.00 488.60 ± 11.48 1574.00 ± 51.28

3.53 −2.28 −1.63

27.98 ± 1.33 510.80 ± 10.06 1618.00 ± 46.04

−6.73 2.16 1.13

28.90 ± 1.76 514.20 ± 13.57 1574.00 ± 51.28

RE (%)

9.73 3.28 1.50 −3.67 2.84 −1.63

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Y. Zhou et al. / Journal of Pharmaceutical and Biomedical Analysis 100 (2014) 294–299

Fig. 2. The mean concentration of analytes versus time profiles after a intravenous infusion of clevidipine butyrate at a dose rate of 17 ␮g/kg/min over a period of 40 min (n = 10) (mean ± SD).

Table 4 Pharmacokinetic parameters of the analytes following single intravenous infusion of clevidipine to Beagle dogs (n = 10). Parameters

Unit

Clevidipine

Cmax Tmax T1/2 AUC0–120 min AUC0−∞ Clz MRT

ng/ml min min ng/ml min ng/ml min l/min/kg min

99.89 22.00 17.38 3779.88 3879.86 0.184 22.70

3.4.4. Extraction recovery and matrix effect Mean extraction recovery (ER) and matrix effect (ME) of analytes are summarized in Table 2 and mean recovery and matrix effect of IS (300 ng/ml) was 87.9% and 95.2%, respectively.

3.4.5. Stability The results of stability are listed in Table 3, which indicate that the analytes were stable under the different storage conditions. No significant deterioration was observed under any of the examined conditions. However, the process of sample preparation should be at a reduced temperature (+4 ◦ C) to avoid the hydrolysis of clevidipine by the small amount of esterases remaining in plasma.

3.5. Pharmacokinetic study The validated LC–MS/MS method was successfully applied to the pharmacokinetic study of clevidipine and its primary metabolite H152/81 after intravenous infusion of clevidipine butyrate at a dose rate of 17 ␮g/kg/min over a period of 40 min to 10 healthy Beagle dogs. The mean plasma concentration–time profiles of clevidipine and H152/81 are shown in Fig. 2, and the related pharmacokinetic parameters are summarized in Table 4.

4. Conclusion For the first time, a novel LC–MS/MS method for the simultaneous determination of clevidipine and its primary metabolite, H152/81 in dog plasma was developed and validated. This method had a higher sensitivity with a lower LLOQ (0.15 ng/ml for clevidipine and 10 ng/ml for H152/81), and a relatively short analytical run time. In conclusion, this validated method was simple, highly sensitive and reliable, and suitable especially for the pharmacokinetic, bioavailability and equivalence study of clevidipine with a large number of samples.

± ± ± ± ± ± ±

H152/81 18.48 9.19 6.42 856.53 865.49 0.044 0.73

689.20 ± 130.91 38.20 ± 4.37 17.53 ± 4.66 29,381.30 ± 5105.07 29,765.41 ± 5032.41 0.024 ± 0.005 37.81 ± 0.97

Acknowledgments The work was supported in part by the important National Science & Technology Specific Projects in the 12th Five year Plan of People’s Republic of China (2011ZX09302-002-01).

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Simultaneous determination of clevidipine and its primary metabolite in dog plasma by liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic study.

A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of ...
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