|Year : 2012 | Volume
| Issue : 1 | Page : 20-25
Pharmacokinetics of venlafaxine and its major metabolite o-desmethylvenlafaxine in freely moving mice using automated dosing/sampling system
Bijay Aryal1, Dipendra Aryal1, Eun-Joo Kim2, Hyung-Gun Kim1
1 Department of Pharmacology, College of Medicine, Dankook University, San#29, Anseo-dong, Dongnam-gu Cheonan, Choongnam, Republic of Korea
2 Department of Pharmacology, Korea Institute of Toxicology, 100 Jangdong, Yuseong Ku, Daejeon, Republic of Korea
|Date of Submission||07-Apr-2011|
|Date of Decision||30-Sep-2011|
|Date of Acceptance||18-Oct-2011|
|Date of Web Publication||14-Jan-2012|
Department of Pharmacology, College of Medicine, Dankook University, San#29, Anseo-dong, Dongnam-gu Cheonan, Choongnam
Republic of Korea
Source of Support: Grant from institute of Bio-Science and Technology (IBST) at Dankook University in 2009., Conflict of Interest: None
Objective: To assess the pharmacokinetics of venlafaxine (VEN) and its major metabolite o-desmethylvenlafaxine (ODV) in freely moving mice using automated dosing/infusion (ADI) and automated blood sampling (ABS) systems. In addition, concentration of VEN and its metabolite ODV were also measured in brain by microdialysis.
Materials and Methods: Venlafaxine was administered directly via jugular vein or gastric catheterization and blood samples were collected through carotid artery. A series of samples with 10 μl of blood was collected from the mouse using ADI/ABS and analyzed with a validated LC-MS/MS system. Extracellular concentrations of VEN and ODV in brain were investigated by using microdialysis procedure.
Results: The bioavailability of VEN was 11.6%. The percent AUC ratios of ODV to VEN were 18% and 39% following intravenous and intragastric administration, respectively. The terminal half-life of venlafaxine was about two hours. Extracellular concentration of VEN contributed 3.4% of the blood amount, while ODV was not detected in dialysate.
Conclusion: This study suggests that besides rapid absorption of VEN, the first-pass metabolism is likely to contribute for its lower bioavailability in the mouse. The proposed automated technique can be used easily to conduct pharmacokinetic studies and is applicable to high-throughput manner in mouse model.
Keywords: Pharmacokinetics, microdialysis, O-desmethylvenlafaxine, venlafaxine
|How to cite this article:|
Aryal B, Aryal D, Kim EJ, Kim HG. Pharmacokinetics of venlafaxine and its major metabolite o-desmethylvenlafaxine in freely moving mice using automated dosing/sampling system. Indian J Pharmacol 2012;44:20-5
|How to cite this URL:|
Aryal B, Aryal D, Kim EJ, Kim HG. Pharmacokinetics of venlafaxine and its major metabolite o-desmethylvenlafaxine in freely moving mice using automated dosing/sampling system. Indian J Pharmacol [serial online] 2012 [cited 2022 Jan 19];44:20-5. Available from: https://www.ijp-online.com/text.asp?2012/44/1/20/91861
| ╗ Introduction|| |
Mouse is an attractive model for many biomedical researches. Availability of various breeds and knockouts that emulate disease states or altered metabolism advocate its importance in pharmacological or pharmacokinetic studies. Being small in size, it requires relatively small quantity of expensive new chemical entities to conduct pharmacokinetic studies. ,
Various methods are available to collect blood from a mouse for pharmacokinetic studies. Among these, a timed-sacrifice or tail-bleed methods are widely used. However, the timed-sacrifice generates inevitable inter-animal variation, whereas tail-bleed limits to fewer samples with low blood volume. , An automated blood sampling (ABS) that generates multiple samples with precision and ease has been successfully applied in rat. ,, The system allows low stressed sample collection from a freely moving animal. An automated drug infusion (ADI) has also been established, which infuses drug with high precision and accuracy. 
Venlafaxine (VEN) is a phenylethylamine derivative used clinically in the management of depression.  It undergoes extensive first-pass metabolism and produces o-desmethylvenlafaxine (ODV) as a major metabolite. , VEN and ODV have been previously quantified in plasma using liquid chromatography with UV, , colometric,  and fluorimetric detection,  and mass spectrometry. , Liquid chromatography tandem mass spectrometry (LC-MS/MS) has been well established as a sensitive, specific and high-throughput analytical technique, which could be used to develop robust analytical method for simultaneously quantifying the drug and its metabolites.
In the present study, we did a pharmacokinetic measurement of VEN by using the ADI and ABS systems in freely moving mice. In addition, concentration of VEN and its metabolite ODV in brain were measured by microdialysis. The concentration of VEN and ODV in the blood and dialysate was analyzed by using a validated LC-MS/MS method.
| ╗ Materials and Methods|| |
Chemicals and Reagents
VEN, ODV, and fluoxetine were purchased from Alembic Limited (Gujarat, India), Toronto chemicals Inc. (North York, Canada) and Sigma-Aldrich (MO, USA), respectively. Acetonitrile and methanol were purchased from Burdick and Jackson Inc. (Muskegon, MI, USA). Water was purified with a Milli-Q water purification system (Millipore, Bedford, MA, USA). All other chemicals used were of analytical grade.
Apparatus and Conditions
The automated blood sampling consisted of a freely moving mouse containment device Raturn TM (BASi, West Lafayette, IN, USA), and an automated blood sampler Culex™ (BASi). The blood samples were collected into a fraction collector HoneyComb™ (BASi). The temperature of the vials in the fraction collector was maintained at 4 o C. Drug infusion was carried out using Empis™ (BASi). Culex™ and Empis™ were operated on Culex™ software (Version 2.00.19_XP) and Empis™ software (Version 1.11.00), respectively. Mouse jugular catheters CX-2022S (BASi) and mouse carotid catheters CX-2052S (BASi) were used. CMA microdialysis system (Stockholm, Sweden) having perfusion pump (CMA 400), fraction collector (CMA 470), microdialysis probe (CMA 11 14/02 Cupr), and guide cannula (CMA 11) was used to perform microdialysis.
LC-MS/MS system was a Varian ProStar™ (Varian Inc., CA, USA) connected to Varian 1200L quadruple. The system control and data analysis were carried out using Varian MS software (Version 6.5, Varian Inc.). Reversed-phase HPLC columns XTerra® (Waters, MO, USA) with specifications 50 mm × 4.6 mm, 5 μm particle size, and 150 mm × 4.6 mm, 5 μm particle size were used for analyzing blood and dialysate, respectively. An isocratic mobile phase consisting solvent A (90% water, 10% acetonitrile, 0.1% formic acid) and solvent B (10% water, 90% acetonitrile, 0.1% formic acid) mixed in a ratio 69/31 (v/v, A/B) was used at the flow 0.38 ml/min. However, dialysate was separated with gradient mobile phase; 0 min (A/B, 20/80), 3 min (A/B, 60/40) and 6 min (A/B, 20/80). To avoid contamination, first two min elution was diverted to discard. The multiple reaction monitoring (MRM) transitions with collision energy (eV) for VEN, ODV, and fluoxetine were 278.4 ® 260.1 (7.5 eV), 264.4 ® 246.1 (7.0 eV), and 310.3 ® 148.1 (6.5 eV), respectively. The scan time and dwell time were 0.6 sec and 0.2 sec, respectively. Electrospray ionization (ESI) was performed under capillary 3000 volts, shield 675 volts and temperature 350 O C, respectively. Manifold temperature and pressure were 42 O C and 0.016 mTorr. Detector was used at 1700 volts.
Animal Handling and Surgery
All experimental protocols involving animals were reviewed and approved by Institutional Animal Care and Use Committee (IACUC) of Dankook University. Male CD-1 mice (Charles River, 20-25g) were purchased and housed for one month with adequate supply of food and water. Surgical procedures were carried out under anesthesia of ketamine and xylazine, 80 mg/kg and 20 mg/kg, respectively. For intravenous study, right jugular vein and left carotid artery were catheterized for infusing drug and collecting blood samples, respectively. Similarly, gastric catheter was implanted to infuse drug for intragastric study. After implanting gastric catheter, mice were allowed to recover for three days and then microdialysis probe was implanted together with guide cannula. The stereotaxic instrument (David Kopf Instruments, CA, USA) was used to implant the probe at co-ordinates AP: 1.3mm, VL: 1.1mm, DL: 2.1mm and then fixed with dental cement Durelon™ (3M ESPE, Germany). The mice were then allowed to recover for two more days. Finally, carotid was catheterized to collect blood samples. Catheters were flushed with heparinized normal saline. Considering the dead volume of catheter, an adjusted dose of VEN (13 mg/kg) was infused at the rate 70 μl/min through jugular or gastric catheter. ABS system was programmed to collect 10 μl of blood with 90 μl of heparinized saline. A series of blood samples were collected at 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360, and 480 min and the loss of blood volume were equally compensated by infusing back with same volume of heparinized saline. The no-loss technique that virtually avoids blood loss was used to collect the blood samples. For intragastric study, an additional 5 min sample was also collected. Microdialysis was carried out at the flow 1.0 μl/min and the dialysate was collected for every 30 min in a micro-vial filled with 10 μl of 10 mM acetic acid. The relative recovery rate of the microdialysis probe (CMA 11 14/02 Cupr) was determined in vitro before microdialysis.
Sample Preparation and Validation
Simulating the samples generated by automated blood sampler, the validation samples were prepared by mixing 1 ml of mouse blood with 9 ml of heparinized normal saline. An aliquot of the blood mixture (90 μl) spiked with 10 μl working solution was then added to 25 μl of fluoxetine (500 ng/ml) as an internal standard (IS). The spiked sample was extracted with 1 ml extraction solvent (diethyl ether/ dichloromethane: 7/3, v/v). The organic layer was dried under gentle stream of nitrogen. The dried extract was reconstituted with 200 μl of methanol-water (50/50, v/v) and 20 μl was injected into the high performance liquid chromatography (HPLC) system.
Lower limit of detection (LOD) was defined as a peak with signal-to-noise ratio (S/N) more than 5/1, while lower limit of quantification (LLOQ) was further narrowed to have percentage coefficient of variation (C.V. %) less than 20%. Triplicates of validation samples at concentrations 0.1, 0.5, 1, 5, 10, and 50 μg/ml were used to draw calibration curve for VEN. Similarly, calibration curve for ODV was drawn from 0.1, 0.5, 1, 5, and 10 μg/ml samples. Quality control samples at 0.1, 1, and 10 μg/ml were used for evaluating extraction recoveries, precision, accuracy, and short-term stabilities. The short-term stability was evaluated for three freeze-thaw cycles within 30 days.
Artificial CSF (CMA, Sweden) was used to prepare validation samples at concentrations 0.01, 0.1, 0.5, and 1 μg/ml. A 30 μl of spiked CSF was treated with 10 μl of acetic acid (10 mM) and 10 μl of IS (500 ng/ml, fluoxetine). A 40 μl aliquot was transferred to the transfer vials and 20 μl was injected into HPLC system. Triplicates of these validation samples were used to draw calibration curves. Similarly, the dialysate was spiked with 10 μl of IS (500 ng/ml, fluoxetine) and then 20 μl was injected.
Noncompartmental pharmacokinetic analysis was performed using WinNonlin™ Professional (Version 2.1, Pharsight, CA, USA). Half-life (t 1/2 ), volume of distribution at steady state (V ss ), and total clearance (C L ) were measured for intravenous study of VEN. Other studies were expressed as area under the concentration-time curve at time t (AUC t ), maximum concentration (C max ) and time to reach maximum concentration (T max ).
| ╗ Results|| |
The chemical structure of VEN and ODv are shown in [Figure 1]. LC-MS/MS chromatograms of VEN and ODV representing blank, limit of detection, and 4 h and 8 h blood samples are shown in [Figure 2]. VEN and ODV were closely eluted, however, specific MRM transitions used in tandem mass allowed these to quantify independently within 2.5 min run time. Coefficients of regression for calibration ranges were greater than 0.998. Although the blood samples collected using ABS system were enriched of electrolytes and heparin, the liquid-liquid extraction was found suitable for minimizing ion-suppression. However, the small volume of the dialysate failed to be extracted using liquid-liquid extraction, a six-port diverting valve was successfully used to divert the preceding electrolytes. The separation was carried out in 150 mm reverse phase column and gradient mobile phase.
|Figure 1: Structure of venlafaxine (VEN) and o-desmethylvenlafaxine (ODV)|
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|Figure 2: LC-MS/MS chromatograms for VEN (a) and ODV (b) at respective multiple reactions monitoring transitions 278.4 → 260.1 and 264.4 → 246.1. Corresponding a, b, c, and d represent extracted blank samples, the lower limit of detection (0.05 μg/ml), blood samples at 8 hours and 0.25 hours following intravenous administrations, respectively|
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The LC-MS/MS method showed good sensitivity, specificity, precision, recovery, and linearity for quantification of VEN and ODV in blood samples. The liquid-liquid extraction was able to extract VEN and ODV with percentage extraction recoveries of 81% and 72%, respectively. The calibration range for VEN and ODV were 0.1 to 50 μg/ml, and 0.1 to 10 μg/ml, respectively and their respective correlation coefficients (r 2 ) were 0.998 and 0.995. The interday and intraday precisions were less than 15 % and 10% for VEN and ODV, respectively. The short-term stability evaluated using three sets of QC samples together with intraday precision samples was within 15% of coefficient of variation which indicated stability of blood samples at least for 30 days. Validation of LC-MS/MS method quantifying venlafaxine (VEN) and its metabolite o-desmethylvenlafaxine (ODV) in the mouse blood samples are shown in [Table 1].
|Table 1: Validation of LC-MS/MS method quantifying venlafaxine (VEN) and its metabolite o-desmethylvenlafaxine (ODV) in the mouse blood samples*|
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Pharmacokinetic Comparison of VEN and ODV
The concentration-time profile of VEN and ODV following intravenous and intragastric administration of VEN are shown in [Figure 3]. The pharmacokinetic parameters of VEN and ODV following intravenous administration are given in [Table 2]. The AUC t of VEN and ODV were 33.66 ± 7.23 and 6.05 ± 2.64, respectively. VEN showed short terminal half-life with relatively high volume of distribution and total clearance. The values of t 1/2 , V ss and C L were 1.34 ± 0.25 h, 0.62 ± 0.16 l, and 0.35 ± 0.09 l/h, respectively. In mice, given an intragastric dose of VEN, the peak concentration was observed at about 2 h indicating rapid absorption from the gut [Table 3]. Bioavailability of intragastric dosing was 11.6% which was similar to the intragastric bioavailability in rats (12.6%). The AUC t of ODV following intravenous and intragastric infusion represented 18% and 39% of VEN, respectively. Following intragastric administration, 3.4% of VEN was quantified in dialysate than that in the blood [Figure 4]. The time to reach maximum concentration of VEN in blood and brain were 2.00 ± 1.47 and 3.50 ± 0.71 h, respectively [Table 3].
|Figure 3: Blood concentration-time curves of VEN (●) and ODV (○) after a bolus dose of VEN (13 mg/kg) using an automated drug infusion, through intravenous (i.v., n=7) or intragastric (i.g., n=5) catheters in mice. Data represented inter-animal variations as mean (± S.D.) in samples collected with an automated blood sampler|
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|Figure 4: Brain concentration-time curve of VEN (●) after a bolus dose of VEN (13 mg/kg) using an automated drug infusion, through intragastric (i.g., n=5) catheters in mice. Data represents inter-animal variations as mean (± standard deviation), in samples collected with a microdialysis system|
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|Table 2: Noncompartmental pharmacokinetic parameters of VEN and ODV following intravenous administration of VEN in mice (13 mg/kg, n=7)|
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|Table 3: Noncompartmental pharmacokinetic parameters of VEN and ODV following intragastric administration of VEN in mice (13 mg/kg, n=5), quantified in blood and dialysate samples|
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A microdialysis probe is a sampling device that contains specific length of semi-permeable dialysis membrane. An implanted probe samples the extracellular fluid around the implanted tissue site. Small unbound drug or neurotransmitters molecules diffuse through the dialysis membrane into the perfusion medium, which is isotonic to the extracellular fluid. The percentage recovery of the analyte is dependent on membrane length, perfusion flow rate, and the nature of the analyte. In this experiment, the probe implanted in the mouse striatum contained a 4 mm length of membrane. In vitro recovery for both VEN and ODV through the brain probe was found to be less than 10%. The relative amount of VEN quantified in dialysate represented only 3.4% of the blood concentration, but ODV was not detected in dialysate [Figure 4].
| ╗ Discussion|| |
Recent advancement in automated blood sampling and sensitive analytical techniques favors possible use of mice in pharmacokinetic studies by generating multiple blood samples collected from a single mouse, and thus, avoiding inter-animal variability. ,, However, collecting multiple blood samples from a mouse is not simple. Common problems include catheter occluded with blood clots, trauma, and infections associated with catheter surgery or retrieval, and positional errors caused by shifting or realignment of the catheter tip within the vein or artery. , Encountering any of these difficulties may result in loss of a timed-sample or loss of life. Overcoming these difficulties, the current study is approaching to establish automated systems for pharmacokinetic studies in mice. ,, During this study, success rates of jugular catheterization, carotid catheterization, gastric catheterization, and microdialysis probe implantation were 100%, 90%, 100%, and 100%, respectively. Performing intravenous study needed two surgeries which dropped success rate to 70%. Similarly, three surgeries needed for intragastric study dropped the success to 50%. However, these were managed to infuse drug through intravenous or intragastric catheters and collect multiple blood samples from carotid catheter in this study. Microdialysis was also conducted in intragastric study.
An analytical approach with LC-MS/MS was able to analyze VEN and ODV in blood samples and dialysate. A liquid-liquid extraction was suitable to avoid ion-suppressing effects of electrolytes present in blood samples collected using ABS system. However, small volume of dialysate disfavored extraction. Previously, direct injection,  column switching,  flow splitting,  and flow diverting  were used to analyze dialysate using LC-MS/MS. Considering the simplicity of the approach, flow diverting was successfully used to analyze dialysate samples.
VEN is a lipid soluble drug with high volume of distribution and low plasma protein binding.  It is highly absorbed through gastrointestinal tract but undergoes first-pass metabolism.  ODV is a primary metabolite of VEN in human, whereas in mouse, it is further conjugated with glucuronide or sulfate.  Consistent with previous findings, , VEN showed lower bioavailability in this study also. Furthermore, the relative amount of quantified VEN in dialysate represented only 3.4% of the blood concentration. The lower relative amount of VEN in dialysate could be explained since dialysate reflects the free drug concentration in extracellular fluid and VEN has been shown to have higher protein binding with the brain parenchyma. 
In summary, the present study successfully utilized automated drug infusion, automated blood sampling, microdialysis, and LC-MS/MS to investigate pharmacokinetic parameters of VEN and ODV in mice. It revealed that mice have high metabolic turnout of VEN on intragastric administration; however, ODV remained at low level. Indeed, the experimental settings used here are conceptually important to advocate mice model for pharmacokinetic and metabolomic studies.
| ╗ Acknowledgement|| |
This work was supported by the grant from institute of Bio-Science and Technology (IBST) at Dankook University in 2009.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]
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