Int J Pharm Pharm Sci, Vol 10, Issue 2, 80-86Original Article


A VALIDATED LC-MS/MS METHOD FOR PHARMACOKINETIC STUDY OF CANAGLIFLOZIN IN HEALTHY RABBITS

DARSHAN BHATT, B. RAJKAMAL

Mewar University, Chittorgarh, Rajasthan, India
Email: darshanbhatt1984@gmail.com

Received: 22 Oct 2017 Revised and Accepted: 21 Dec 2017


ABSTRACT

Objective: A liquid chromatography-tandem mass spectrophotometric (LC-MS/MS) method was developed for quantification of canagliflozin in rabbit plasma employing Liquid-Liquid extraction technique.

Methods: Chromatographic separation was achieved on Inertsil ODS 5 µm C18, 50×4.60 mm with 30:70 v/v of 0.01M ammonium acetate: methanol as an isocratic mobile phase with a flow rate of 0.8 ml/min. The developed LC-MS method was applied to assess Cmax, t1/2, AUC0-t, and AUC0-inf of canagliflozin tablet after oral administration in healthy rabbits.

Results: The developed method was linear over working range of 5ng/ml to 600ng/ml with a coefficient of correction (r2) = 0.999. The % recovery of the method was found to be 102.05%. The mean intraday and inter-day precision of the method was found to be 0.77 to 3.72%. The Canagliflozin showed Tmax of 1.58±0.2 and mean Cmax, AUC0→t and AUC0→α for Test formulation is 272±13.24, 2571.20±251and 2777.43±276 respectively.

Conclusion: The developed method can be applied for routine analysis for quality control and the established LLOQ is sufficiently low to conduct a pharmacokinetic study with any marketing formulation of Canagliflozin in healthy rabbits.

Keywords: Canagliflozin, Pharmacokinetics, LC-MS/MS, Diabetes mellitus


INTRODUCTION

Canagliflozin, an orally active inhibitor of sodium glucose co-transporter 2 (SGLT2), is currently in development for the treatment of patients with type 2 diabetes mellitus [1-2]. Inhibition of SGLT2 causes inhibition of glucose reabsorption in renal proximal tubular cells, thereby reducing the renal threshold for glucose (RTG) [3-4]. As per the Literature Survey, it is revealed that the Ultraviolet spectroscopy (UV), High-Performance Liquid Chromatography (HPLC) and High-Performance thin layer Chromatography (HPTLC) methods were reported for degradation studies and to estimate the canagliflozin from bulk and Pharmaceutical dosage forms [5-10]. Ultra High Performance/liquid Chromatography-Mass Spectroscopy (UHPLC-MS and LC-MS/MS) methods were reported for quantification of the drug in biological fluids like human and rat plasma [11, 12]. To best of our knowledge, no published LC-MS/MS-based methods for the pharmacokinetic study of canagliflozin in healthy rabbits. Therefore a liquid chromatography-tandem mass spectrophotometric (LC–MS/MS) method was developed, validated and applied for quantification of canagliflozin in rabbit plasma employing liquid-liquid extraction (LLE) technique. The established LLOQ is sufficiently low to conduct a pharmacokinetic study with any marketing formulation of canagliflozin in human volunteers.

MATERIALS AND METHODS

Apparatus and software

The HPLC system with an autosampler was a shimadzu LC-20ADvp, shimadzu, japan, coupled with applied bio system sciex, MDS Sciex, Canada, API 4000 tandem mass spectrometer. The autosampler was SIL-HTC from shimadzu, Japan. The solvent delivery module was LC-20AD from shimadzu, Japan. The chromatographic integration was performed by analyst software, version: 1.4.2; applied bio systems.

Chemicals and reagents

Canagliflozin and empagliflozin (IS) were obtained on request from MSN Life Sciences Pvt. Ltd. Hyderabad and Mylon laboratories, Hyderabad respectively, formic acid were procured from Merck Specialities Pvt. Ltd, Mumbai, India. Water used was collected from water purification systems (Milli Q, Milli Pore, USA) installed in the laboratory. Methanol and acetonitrile were of HPLC grade and were supplied by J. T. Baker, USA. Hyderabad. The plasma was obtained from rabit blood by freeze centrifugation. The study was approved by institutional ethical committee no: VCP/IAEC/2016-48.

Calibration standard solutions

Stock solutions of canagliflozin and empagliflozin internal standard (IS) were prepared in methanol. Further dilutions were carried out in 70 % methanol. Calibration standards of eight concentration levels were prepared freshly by spiking drug-free plasma with canagliflozin stock solution to give the concentrations of 5.00, 10.00, 20.00, 40.0, 100, 200, 400 and 600ng/ml.

Quality control standards

Lowest quality control standards, median quality control standards and highest quality control standards were prepared by spiking drug-free plasma with canagliflozin to give a solution containing 10, 300 and 500 ng/ml respectively. They were stored at-20 °C till the time analyzed.

Chromatographic conditions

Chromatographic separation was performed on inertsil ODS 5 µm C18, 50×4.60 mm with 30:70 v/v of 0.01M ammonium acetate: methanol as an isocratic mobile phase with a flow rate of 0.8 ml/min. Injection volume was 5μl. Total analysis time of single injection was 2.00 min. Column oven temperature and autosampler temperature was set to 40 °C and 5 °C, respectively.

Mass spectrometric conditions

The LC eluent was split (75%), and approximately 0.25 ml/min was introduced and quantitation was achieved with MS/MS detection in negative ion mode for the analytes and IS using a MDS Sciex API-4000 mass spectrometer (Foster City, CA, USA) equipped with Turboion spray interface at 400 °C. The ion spray voltage was set at 5500 V. The source parameters viz., the nebulizer gas, curtain gas, CAD gas were set at 8, 10 and 6 psi, respectively. The compound parameters viz. the declustering potential (DP), collision energy (CE), entrance potential (EP) and collision cell exit potential (CXP) for canagliflozin and canagliflozin-D3 were similar and are 18, 10, 10, 10 V. A turbo ion spray interface (TIS) operated in positive ionization mode was used for the detection. Detection of the ions was carried out in the multiple-reaction monitoring mode (MRM), by monitoring the transition pairs of m transitions of m/z 462.1→267.0 for canagliflozin, and m/z 451.2 →71.0 for empagliflozin. Quadrupoles Q1 and Q3 were set on the unit resolution.

Study design

Six male albino rabbits (Weighing about 2.5 kg) procured by vijaya college of pharmacy which was obtained from the approved vendor. The rabbits selected for the study was approved by institutional ethical committee no: VCP/IAEC/2016-48. The age of the rabbits was 8-12 w and had no medication for two weeks prior to the study. Twelve hours before drug administration, food was withdrawn from the rabbits until 24 hr post-dosing, while, water was available for rabbits throughout the study. The tablet with the dose of 13 mg based on the animal surface area was administered to rabbits. T-Blood samples (0.6 ml) were withdrawn from the marginal ear vein before dosing (zero time) and at time intervals of 0.15, 0.25,0.5 0.75, 1,1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 20 and 24 h after administration. For each animal, the total number of blood samples drawn during the study was 18. EDTA disodium salt was used as an anticoagulant. Plasma was separated by centrifugation at 5000 rpm for 10 min and the resulting plasma sample from each blood sample was divided into two aliquots and stored in suitably labelled polypropylene tubes at 20 °C until used. All the plasma samples were analysed under the construction of standard calibration curve of canagliflozin in rabbit’s plasma. The canagliflozin concentrations in the rabbit plasma samples were calculated using the calibration curve, obtained after linear regression of the peak area ratio (canagliflozin/empagliflozin) versus the concentration of canagliflozin.

Sample preparation method

To 250 µl of plasma, 50 µl of empagliflozin (50ng/ml) was added and vertexed. The drug was extracted with 3 ml of TBME (tertiary butyl methyl ether) followed by centrifugation at 2000 rpm/min on a cooling centrifuge for 15 min at 4 °C. The organic phase was withdrawn and dried using lyophiliser. To the residue, 250 µl of mobile phase was added and inject by using HPLC-ESI-MS/MS.

Pharmacokinetic analysis

Single dosage pharmacokinetic parameters were calculated using PK Solver tool from plasma drug concentration-time data by non-compartmental methods. The maximum plasma concentration (Cmax) and time to maximum plasma concentration (Tmax) were obtained directly from the observed concentration-time profiles. The linear trapezoidal rule was used to estimate the area under the plasma concentration versus time curve (AUC) from 0 to the last measurable concentration (AUC 0-t). The area under the plasma concentration versus time curve from 0 to infinity (AUC 0-∞) was calculated as AUC 0-t+Ct/ke, where Ct was the last measurable concentration. Ke was the elimination rate constant. The terminal elimination half-life (t1/2) was calculated as 0.693/Ke.

Validation

Specificity

A solution containing 4.0ng/ml was injected on to the column under optimized chromatographic conditions to show the separation of canagliflozin from impurities and plasma. The specificity of the method was checked for the interference from plasma.

Linearity

Spiked concentrations were plotted against peak area ratios of canagliflozin to the internal standard and the best fit line was calculated. Wide range calibration was determined by solutions containing 5ng/ml to 600ng/ml.

Recovery

The % mean recoveries were determined by measuring the responses of the extracted plasma Quality control samples at HQC, MQC and LQC against unextracted Quality control samples at HQC, MQC and LQC.

Precision and accuracy

Intraday precision and accuracy was determined by analyzing quality control standards (10, 300and 500ng/ml) and LLOQ Quality control standard (4.00 ng/ml) five times a day randomly, interday precision and accuracy was determined from the analysis of each quality control standards (10, 300and 500ng/ml) and LLOQ quality control standards (4.00 ng/ml) once on each of five different days.

Matrix effect

The matrix effect for the intended method was assessed by using chromatographically screened human plasma. Concentrations equivalent to LQC and HQC of canagliflozin were prepared with six different lots of plasma and are injected.

Stability studies

The stability of canagliflozin was determined by measuring concentration change in control samples overtime under set conditions. Freeze-thaw stability study (-80 °C) of canagliflozin was carried out by subjecting samples to three freeze and thaw cycles. Samples before the study and after study were analysed by developed method. Similarly stock solution stability study of canagliflozin (Stability after 6 H), Long-term stability (-80 °C, 30days), benchtop stability study of canagliflozin (at ambient temperature, 6h), dry residue stability(4 °C, 48h) and Auto-sampler stability (4 °C, 24h) of canagliflozin were carried out by subjecting samples to study conditions.

RESULTS AND DISCUSSION

Results of method validation

The chromatography observed during the course of validation was acceptable and representative chromatograms of standard blank, HQC, MQC and LQC samples are shown in (fig. 1-4).

Fig. 1: Representative blank chromatograms of canagliflozin and IS in blank plasma

Fig. 2: Representative HQC-chromatograms of canagliflozin in plasma with internal standard

Fig. 3: Representative MQC-chromatograms of canagliflozin and its internal standard

Fig. 4: Representative chromatograms of canagliflozin and its internal standard at LQC Level

Fig. 5: Calibration curve

Table 1: Summary of linearity standards for canagliflozin

Actual conc. (ng/ml) 4 8 25 50 100 150 300 600 Slope Intercept
1 3.95 7.73 25.02 50.9 102.7 150.33 309.5 586.5 0.983 2.493
2 3.875 7.73 25.25 49.96 100.53 148.67 315.5 588.75 0.99 1.854
3 3.975 7.86 25.44 49.23 98.76 147.67 307 582 0.976 1.729
Mean 3.93 7.78 25.24 50.03 100.67 148.89 310.67 585.75 0.983 2.025
±SD* 0.052 0.077 0.208 0.835 1.970 1.347 4.368 3.436 0.007 0.409
%CV** 1.32 0.99 0.83 1.67 1.96 0.90 1.41 0.59
% Accuracy 98.33 97.22 100.96 100.06 100.66 99.25 103.55 97.625
LOD*** 1.38
LOQ**** 4.17

*Standard deviation, **coefficient of variation, ***limit of detection, ****limit of quantification.

The method developed was validated for linearity, accuracy and precision, and stability as per ICH guidance [13-19]. The results of validating parameters are given below.

Linearity

The three calibration curves (peak area ratio Vs concentration) were linear over working range of 5ng/ml to 600ng/ml with eight-point calibration used for quantification by linear regression (fig 5 and table 1). The regression equation for the analysis was 0.983x-2.025with coefficient of correction (r2) = 0.999.

Recovery

The % mean recovery for canagliflozin in LQC (10 ng/ml), MQC(300 ng/ml) and HQC (500ng/ml) was 95.83%, 103.97% and 106.35% respectively (table 2).

Intraday and inter-day precision

The mean intraday and inter-day precision of the method was found to be 0.77 to 3.72% for the quality control samples. This is within the acceptance limits of precision is 15% (table 3).

Table 2: The % mean recovery of canagliflozin for LQC, MQC and HQC

 ID LQC MQC HQC

Un

extracted

Extr

acted

%

recovery

Un

extracted

Extracted

%

recovery

Un

extracted

Extr

acted

%

recovery

  (area ratio) (area ratio) (area ratio) (area ratio) (area ratio) (area ratio)
1 0.164 0.151 92.073 0.956 0.984 102.93 2.077 2.158 103.90
2 0.161 0.146 90.683 0.97 0.992 102.27 2.117 2.16 102.03
3 0.147 0.144 97.959 0.977 0.977 100.00 1.914 2.144 112.02
4 0.157 0.153 97.452 0.922 0.98 106.29 2.048 2.151 105.03
5 0.146 0.145 99.315 0.927 0.985 106.26 1.989 2.096 105.38
6 0.163 0.159 97.546 0.932 0.989 106.12 1.973 2.166 109.78
Mean 0.156 0.150 95.838 0.947 0.985 103.977 2.020 2.146 106.356
±SD* 0.008 0.006 3.546 0.023 0.006 2.644 0.075 0.026 3.774
%CV** 5.11 3.87 3.70 2.48 0.56 2.54 3.70 1.19 3.55

*Standard deviation, **coefficient of variation.

Matrix effect

The % CV for HQC and LQC samples was observed 3.39% and 2.39% respectively (table 4), which are within 15% as per the acceptance criteria.

Stability studies

The Stability studies were assessed using quality control samples (HQC and LQC) and the %mean stability for HQC and LQC were presented which is within the acceptance limits of 85 to 115% (table 5).

Pharmacokinetic studies

The Pharmacokinetic parameter of canagliflozin was calculated from the plasma concentration-time curves using pk solver software. Also, the area under the plasma concentration-time curve from 0 to 24hr (AUC0-24) was calculated using trapezoidal rule. Canagliflozin showed Tmax of 1.58±0.2 and mean Cmax, AUC0→t and AUC0→α for Test formulation is 272±13.24, 2571.20±251and 2777.43±276 respectively. The results were presented in table 6, table 7 and fig. 6.

Table 3: Intra-day and inter-day quality control samples for canagliflozin

QC Canagliflozin (ng/ml)(n=6)

Intra-batch

 

LLOQ QC LQC MQC HQC
(5ng/ml) (10ng/ml) (300ng/ml) (600 ng/ml)
Mean* 4.93 10.59 293.70 618.53
SD** 0.0520416 0.33 6.04 4.79
%CV*** 1.05 3.16 2.06 0.77
Mean 5.183333 9.10 301.13 635.24
SD 0.052042 0.34 6.03 7.38
%CV 1.004019 3.72 2.00 1.16
Mean 4.703333 10.15 295.82 620.89
SD 0.052042 0.37 5.62 9.27
%CV 1.106484 3.64 1.90 1.49
Inter-batch LLOQ QC LQC MQC HQC
  (5ng/ml) (10ng/ml) (300ng/ml) (600 ng/ml)
Mean 4.783333 0.25 2.66 5.47
SD 0.052042 0.00 0.08 0.08
%CV 1.087979 3.22 3.06 1.47

*Average of six determinations, **standard deviation, ***Coefficient of variation.

Table 4: Matrix effect obtained with six different lots of plasma

QCID LQC HQC
Actual conc. (ng/ml) 10 600
1 11.08 612.5
2 10.95 608.9
3 10.5 603.3
4 10.83 604.8
5 11.54 586.5
6 10.62 631.3
Mean 10.92 607.8
±SD* 0.37 14.55
% CV** 3.39 2.39
% accuracy 109.24 101.31

*Standard deviation, **coefficient of variation

Table 5: Results of stability studies

Stability condition Nominal Calculated concentration
Concentration (ng/ml) Mean*±SD** % Bias
Freeze-thaw stability
(-80 oC)
10 10.77±0.211 7.7
600 594±7.86 -1
Long-term stability
(-80 oC, 30days)
10 9.63±0.169 -3.7
600 594±20.8 -1
Autosampler Stability
(4 oC, 24h)
10 9.69±0.204 -3.1
600 591±12.0 -1.5
Bench Top stability (6h) 10 9.22±0.411 -7.8
600 582±6.56 -3
Dry residue stability (4 oC, 48h) 10 9.83±0.121 -1.7
600 591±10.4 -1.5
Autosampler Stability
(4 oC, 24h)
10 9.44±0.221 5.5
600 589±8.0 -1.833333
N=6    

*Average of six determinations, **standard deviation

Table 6: Calculated plasma concentrations in rabbits at each time point

Time points (h) Calculated concentrations (ng/ml)
Rabbit 1 Rabbit 2 Rabbit 3 Rabbit 4 Rabbit 5 Rabbit 6 Mean SD*
0 0 0 0 0 0 0 0 0.00
0.15 24 15 30 21 18 12 20 6.48
0.25 48 54 57 36 45 54 49 7.75
0.5 102 87 96 93 111 102 98.5 8.36
0.75 156 174 180 174 156 168 168 10.04
1 213 243 237 207 195 207 217 18.85
1.5 252 288 273 261 279 267 270 12.87
2 231 249 267 246 264 279 256 17.25
2.5 204 225 228 210 228 243 223 14.03
3 189 174 219 198 207 234 203.5 21.42
4 174 162 192 186 186 201 183.5 13.74
5 165 183 183 171 162 147 168.5 13.74
6 156 168 171 147 141 123 151 17.97
8 147 159 150 126 108 105 132.5 22.88
12 138 147 135 120 99 96 122.5 21.25
16 102 114 114 93 75 66 94 20.05
20 27 18 24 15 18 27 21.5 5.17
24 0 0 0 0 0 0 0 0.00

*Standard deviation.

Table 7: Calculated mean values of PK parameters for test animals

Parameter Mean* (n=6) SD**
Lambda_z 0.11 0.01
t1/2 6.56 0.74
Tmax 1.58 0.20
Cmax 272.00 13.24
AUC 0-t 2571.20 251.54
AUC 0-inf_obs 2777.43 275.93
Vz/F_obs 0.04 0.00
Cl/F_obs 0.00 0.00

*Average of six determinations, **standard deviation

Fig. 6: Plasma concentration-time profile of test animals

DISCUSSION

The established LC-MS/MS method has high selectivity, sensitivity and linear with least LLOQ (5ng/ml) concentration and have good % mean recovery (102.05%) when compared to other reported method for the estimation of canagliflozin metabolites from human plasma and another biological matrix. [11-12]. Liquid-liquid extraction technique was employed to reduce the interference from plasma. As per literature review, no LC-MS/MS method was available for determination of canagliflozin alone from rabit plasma, the validated method has great importance to determine the pharmacokinetic parameters of canagliflozin.

CONCLUSION

The bio-analytical methodology for determination of canagliflozin described in this manuscript is highly specific, rugged and rapid for therapeutic drug monitoring both for analysis of routine samples of a single dose or multiple dose pharmacokinetics and also for clinical trial samples with desired sensitivity, precision, accuracy and high throughput. The method involved a simple and specific sample preparation by liquid-liquid extraction followed by isocratic chromatographic separation in 2.0 min. The overall analysis time is promising compared to other reported procedures for canagliflozin. The established LLOQ is sufficiently low to conduct a pharmacokinetic study with any marketing formulation of canagliflozin in healthy rabbits.

AUTHORS CONTRIBUTIONS

The corresponding author Mr. Darshan Bhatt, Research Scholar, Mewar University, Chittorgarh, Rajasthan, India, who completed the intended research work under the guidance of his guide Dr. B. Rajkamal,Research Supervisor, Mewar University, Chittorgarh, Rajasthan, India

CONFLICT OF INTERESTS

Declared none

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About this article

Title

A VALIDATED LC-MS/MS METHOD FOR PHARMACOKINETIC STUDY OF CANAGLIFLOZIN IN HEALTHY RABBITS

Keywords

Canagliflozin, Pharmacokinetics, LC-MS/MS, Diabetes mellitus

DOI

10.22159/ijpps.2018v10i2.23245

Date

01-02-2018

Additional Links

Manuscript Submission

Journal

International Journal of Pharmacy and Pharmaceutical Sciences
Vol 10, Issue 2, 2018 Page: 80-86

Online ISSN

0975-1491

Authors & Affiliations

Darshan Bhatt
Mewar University, Chittorgarh, Rajasthan, India
India

B. Rajkamal
Mewar University, Chittorgarh, Rajasthan, India
India


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