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ORIGINAL ARTICLE
Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 15-18  

No impact of neuropathy on pharmacokinetic of lamotrigine in rat model


1 Department of Pharmaceutics, University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, India
2 Department of Pharmacy, KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, Andhra Pradesh, India

Date of Web Publication16-Jul-2014

Correspondence Address:
Hema Veesam
Department of Pharmacy, KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada 520 010, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-9234.136779

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   Abstract 

Purpose: The aim of the present research is to monitor any alteration in the serum concentrations of lamotrigine (LMT) in peripheral neuropathic conditions compared with normal conditions in a rat model. Materials and Methods: LMT concentrations were established at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h post dose by high performance liquid chromatography-ultraviolet. After per oral administration of 10 mg/kg drug, pharmacokinetic parameters were determined from plasma drug concentration. Later pharmacokinetic parameters of neuropathic pain induced rats were calculated in order to estimate the possible effect of neuropathic pain on pharmacokinetic parameters. Results: The regression coefficient determined for LMT calibration curve was 0.99 ± 0.001. The working range for LMT was 0.5 to 2.5 μg/ml Limit of Detection (LOD 0.2 μg/ml). The maximum drug concentration was found at 2 h. Conclusion: However, none of the pharmacokinetic parameter showed statistically significant alteration where the results were quite stimulating for the development of clinically useful oxcarbazepine dosage form to explore its activity on neuropathic pain.

Keywords: Chronic constriction injury, lamotrigine, neuropathic pain, pharmacokinetics parameters


How to cite this article:
Avula PR, Veesam H. No impact of neuropathy on pharmacokinetic of lamotrigine in rat model. J Pharm Negative Results 2014;5:15-8

How to cite this URL:
Avula PR, Veesam H. No impact of neuropathy on pharmacokinetic of lamotrigine in rat model. J Pharm Negative Results [serial online] 2014 [cited 2019 Nov 18];5:15-8. Available from: http://www.pnrjournal.com/text.asp?2014/5/1/15/136779


   Introduction Top


Lamotrigine (LMT) is poorly water soluble drug [1] and highly soluble in 0.1N hydrochloric-acid. In all of the deeds, consideration of pharmacokinetics is paramount where it is the analysis of how the body affects a drug. In in-vivo the combined use pharmacokinetic assessment and animal models help to assess the compound efficacy. [2] Neuropathic pain is pain initiated by a primary lesion. [3] Newer antiepileptic drugs possess potential advantages of fewer drug-drug interactions [4] with suitable therapeutic modalities to relieve pain: [5] However, LMT can act as mono-therapy on neuropathic pain. Medical reports on drug kinetics in peripheral neuropathy are often hazy, because it is complicated to perform systematic pharmacokinetic studies in patients with neuropathic pain. This difficulty was due to inter-individual inconsistency in injury extent and location. Thus, experimental models appear to be a suitable strategy for understanding pharmacokinetic alteration and also that the minimal effectual exposure in rats is within 1-15 fold greater than in humans. [6] The present research was designed to study whether the pharmacokinetics of LMT were altered by peripheral neuropathy.


   Materials and methods Top


Chemicals

LMT active pharmaceutical ingredient was gifted by Novartis, Mumbai, India. Solvents used for quantification were of high performance liquid chromatography (HPLC) grade (Merck, India). Remaining all other chemicals and reagents were of analytical grade.

Animals

Either sex of Wistar rats (180-210 g, n = 3) obtained from National Institute of Nutrition, Hyderabad, India was housed under 12:12 h light-dark cycle with food and water ad libitum and acclimatized for 1 week. The experimental protocol was approved by an Institutional Animal Ethics Committee of BITS-Pilani, Hyderabad (IAEC/RES/06/03).

Surgical procedures

Neuropathic pain was induced to rats by chronic constriction injury as previously described by Bennett. [7] Briefly, this surgical procedure involved tying four loose ligatures around the left sciatic nerve at the mid-thigh region. After this procedure, the animal developed a peripheral neuropathy, which resembles the human condition in its response to static, allodynia and hyperalgesia.

Experimental design

The human dose was extrapolated to animal dose using the US Food and Drug Administration dose calculator. [8] The animals were divided into two groups with three animals in each group. Group I contain healthy rats were as Group II consists of neuropathy induced rats.

Drug administration and blood sampling

During this investigation, LMT alone containing 10 mg/kg of the drug was administrated per oral (p.o.) to rats through a ball tipped needle using 1 mL of 20% polyethylene glycol solution as a vehicle. Blood samples (0.5 mL) were withdrawn prior to dosing and at 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 h post-dose from retro-orbitol plexus into centrifuge tubes containing 0.1 mL of 2.8% sodium citrate solution as an anticoagulant. Plasma was separated by centrifuging at 3,000 rpm for 3 min and stored at −20°C until further analysis.

Determination of LMT by HPLC

Plasma LMT was measured using a validated HPLC method as given by Torra et al. [9] Briefly the HPLC system (Water Co., Massachusetts), consisted of waters auto-sampler, a water 2691 separation module pump, 2487 dual lambda ultraviolet detector operated at 210 nm. The stationary phase was waters symmetry C 18 column (150 mm *4.6 mm, 5 μm). Mobile phase used was 5 mM of pH 3 buffer: acetonitrile (55:45 v/v) at a flow rate of 0.8 mL/min.

Data analysis

Pharmacokinetic parameters were calculated by the non-compartment model using Try Kinetica PK-PD 5.0 program. The plasma LMT concentration versus time curves was used to determine the maximum plasma concentration (C max ) and time to achieve maximum plasma concentration (T max ) from the graph. Area under the plasma concentration-time (AUC 0-t ) was calculated using the trapezoidal rule from zero to the last measured plasma concentration (C last ). The terminal elimination rate constant, β, was estimated using linear least square regression of log linear phase of concentration-time curves considering the last four experimental points. Area under the concentration-time curve to respective sampling point was calculated by adding C last /β to AUC 0-t . Mean residence time of the drug (MRT) was calculated from the area under the plasma concentration and area under moment curve, half-life (t 1/2 ) and total body clearance (Cl T ) were also calculated.

Statistical analysis

The difference in pharmacokinetic parameters of LMT was evaluated by a graph-pad prism 5.0 version at P < 0.05 with 95% confidence intervals. Two-way ANOVA followed by Bonferroni post hoc multiple comparison test was performed to find the significance of LMT on normal and diseased rats.


   Results Top


Pharmacokinetics of LMT alone on normal rats

Plasma concentration versus time curve of LMT alone was depicted in [Figure 1]. Pharmacokinetic parameters of LMT were mentioned in [Table 1]. After p.o. administration of LMT alone the observed time to peak LMT levels was at 2 ± 0.001 h with 4.24 ± 0.003 μg/ml of maximum concentration. After initial absorption phase plasma concentration of LMT decreased gradually till 24 h. Time of drug residence in the body was found to be 33 h until 0.072 L of drug clearance per hour and 12 h of elimination t 1/2 . The total volume of drug distributed in the body was 1.28 L.
Figure 1: Plasma drug concentration vs. time plot for lamotrigine alone on (a) normal rats; (b) neuropathic rats. Plasma concentration time curves of lamotrigine following its oral administration at 10 mg/kg to Wistar rats. Data were expressed as mean ± SEM (n = 3)

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Table 1: Categorization of drug promotional literatures according to pharmacological groups (n=100)


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Pharmacokinetics of LMT alone on neuropathic pain induced rats

Plasma concentration versus time curve of LMT alone and dosage forms on diseased rats were shown in [Figure 1] Pharmacokinetic parameters of LMT alone in healthy and diseased rats were shown comparatively in [Table 1]. Upon p.o. administration of LMT for neuropathic pain induced rats, the observed time to peak LMT levels was at 2 h with a maximum plasma concentration of 4.23 ± 0.005 μg/mL. After initial absorption phase plasma concentration of LMT declined gradually. There was no significant alteration in pharmacokinetic parameters such as AUC 0-12 was found to be 69.32 ± 0.16 h* μg/mL, AUMC 0-12 was found to be 726.81 ± 1.82 h 2 * μg/mL, MRT was found to be 32.94 ± 0.5 h thus, there was no significant alteration in any of the pharmacokinetic parameters such as C max , AUC and MRT of LMT alone on neuropathic pain induced rats compared to normal rats.


   Discussion and conclusion Top


This investigation was mainly intended to evaluate the pharmacokinetic profiles of LMT alone on normal rats and neuropathic pain induced rats. The various pharmacokinetic parameters were calculated by the optimal extra-vascular descriptive model fit utilizing the less available data and help to predict even most basic parameters such as MRT, AUC and C max . Furthermore the results clears that there were no alterations in basic pharmacokinetic parameters such as the obtained elimination rate constant, elimination t 1/2 and Cl T obtained results were in correlation with those of the results already reported. The data for LMT revealed that the maximum drug concentration obtained was found to be similar to that demonstrated by Theis et al., [10] but the time to peak concentration was at 1h probably this was obtained from large population between 0.5 h and 2.5 h. From early trial phase 3 studies performed, the therapeutic anticonvulsant serum concentration was between 1-4 μg/mL and 3-14 μg/mL has proven to be quite safe but few [11],[12],[13] reported that concentration above 12 μg/mL was optimum probably such a high concentration may be required depending upon patients and their side effects. There was a direct relationship between daily dose, plasma level of LMT and analgesic effects, which was previously explained by Lunardi et al. [14] Although only a few animals were used per treatment group, the effects seen were consistent across the groups and based on ethical grounds. Butler et al. [15] demonstrated that oral dosing of LMT in rats in excess of the equivalent therapeutic dose in man (>10 mg/kg) does not produce the anticipated increase in the plasma concentration of drug in plasma. Our data clearly demonstrate that an oral dose of 10 mg/kg satisfied the absolute requirement for free drug/plasma concentration. The terminal t 1/2 obtained was 11-22 h in rats correlated with the results previously obtained. [16],[17],[18] The single dose of the drug was found to be sufficient to show the therapeutic efficacy as previously described by Garnett [19] as the pharmacokinetic profile found to be linear and kinetic parameters after multiple dosing were similar to those observed after a single dose. Because of the physiological properties of the drug it has become an interesting analgesic, because it inhibits the release of excitatory neurotransmitters; thus, it was used to study on neuropathic pain. Efficacy in pain models is reported following a single dose of the drug; however, many pain conditions are chronic in nature. Thus, we must ensure that the dosage form offer improved efficacy, enhanced pharmacodynamic effects and not altered pharmacokinetic parameters, such as accumulation, leading to increased drug t 1/2 or exposure. According to the pharmacokinetic data obtained from disease induced rats, there was no significant alteration in any of the key determinants, which include C max , T max and AUC likewise there was no alteration in other potential measures such as K E , t 1/2 and Cl T . Overall, the pharmacokinetic parameters of LMT alone on a rat model explored the better PK profile during diseased conditions. Further, this study also served as an initial step towards identifying that there was no impact of peripheral neuropathy in alteration of pharmacokinetic parameters compared with normal conditions.


   Acknowledgments Top


The authors are thankful to Dr. P. Yogeeswari, Head, Department of Pharmacy, BITS-Pilani, Hyderabad, India for kind support to carry out the work. The authors would like to extend their thanks to Dr. Siva Reddy, Professor, KVSR SCOPS, Vijayawada, India for his constant encouragement throughout the work.

 
   References Top

1.Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413-20.  Back to cited text no. 1
    
2.Whiteside GT, Adedoyin A, Leventhal L. Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology 2008;54:767-75.  Back to cited text no. 2
    
3.Mersky H, Bogduk N. In: Mersky H, Bogduk N, editors. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2 nd ed. Seattle: IASP press; 1991.  Back to cited text no. 3
    
4.Pappagallo M. Newer antiepileptic drugs: Possible uses in the treatment of neuropathic pain and migraine. Clin Ther 2003;25:2506-38.  Back to cited text no. 4
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5.Backonja M. Treatment of neuropathic pain by anticonvulsants. Curr Pain Headache Rep 2003;7:39-42.  Back to cited text no. 5
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6.Garth W, Jeffrey K. Consideration of pharmacokinetic and pharmacodynamic relationships in the discovery of new pain drugs. In: Kruger L, Light AR, editors. Translational pain research: From Mouse to Man. Seattle, USA: CRC Press Book; 2010. p. 109.  Back to cited text no. 6
    
7.Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107.  Back to cited text no. 7
    
8.USFDA, Guidance for industry, estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Pharmacology and Toxicology. US Department of health and human services, FDA, Rockville, MD, USA; 2005.  Back to cited text no. 8
    
9.Torra M, Rodamilans M, Arroyo S, Corbella J. Optimized procedure for lamotrigine analysis in serum by high-performance liquid chromatography without interferences from other frequently coadministered anticonvulsants. Ther Drug Monit 2000;22:621-5.  Back to cited text no. 9
    
10.Theis JG, Sidhu J, Palmer J, Job S, Bullman J, Ascher J. Lack of pharmacokinetic interaction between oxcarbazepine and lamotrigine. Neuropsychopharmacology 2005;30:2269-74.  Back to cited text no. 10
    
11.Morris RG, Black AB, Harris AL, Batty AB, Sallustio BC. Lamotrigine and therapeutic drug monitoring: Retrospective survey following the introduction of a routine service. Br J Clin Pharmacol 1998;46:547-51.  Back to cited text no. 11
    
12.Johannessen SI, Battino D, Berry DJ, Bialer M, Krämer G, Tomson T, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003;25:347-63.  Back to cited text no. 12
    
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14.Lunardi G, Leandri M, Albano C, Cultrera S, Fracassi M, Rubino V, et al. Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia. Neurology 1997;48:1714-7.  Back to cited text no. 14
    
15.Butler P, Gardiner JC, Loftus JP, Karran E, Roffey SJ, Gupta P, et al. A comparison of the effects of lamotrigine on neuroma-induced action potential firing and normal behaviour in rat: Implications for establishing a pre-clinical 'therapeutic index'. Neurosci Lett 2001;304:13-6.  Back to cited text no. 15
    
16.Parsons DN, Dickins D, Morley TJ. Lamotrigine: absorption, distribution and excretion. In: Levy RH, Maltson RH, Meldrug BS, editors. Antiepileptic Drugs. New York: Raven Press; 1995. p. 877-81.  Back to cited text no. 16
    
17.Perucca E. The clinical pharmacology of the new antiepileptic drugs. Pharmacol Res 1993;28:89-106.  Back to cited text no. 17
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18.Garnett WR. Lamotrigine: Pharmacokinetics. J Child Neurol 1997;12 Suppl 1:S10-5.  Back to cited text no. 18
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19.Devulder J. The relevance of monitoring lamotrigine serum concentrations in chronic pain patients. Acta Neurol Belg 2006;106:15-8.  Back to cited text no. 19
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]


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