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  In this Article
   Abstract
   Introduction
   Material and methods
   Results
   Discussion
   References

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Year : 2002  |  Volume : 50  |  Issue : 1  |  Page : 60-2

Correlation of serum and salivary carbamazepine concentration in epileptic patients : implications for therapeutic drug monitoring.


Department of Pharmacology, Maulana Azad Medical College, New Delhi, 110002, India.

Correspondence Address:
Department of Pharmacology, Maulana Azad Medical College, New Delhi, 110002, India.

    Abstract

Therapeutic drug monitoring (TDM) of carbamazepine (CBZ) in saliva is an attractive alternative, because its collection is painless, non-invasive and simpler than drawing blood. Salivary drug levels, also closely reflect the free drug concentration. The aim of the study was to evaluate the suitability of saliva in routine TDM of CBZ in adult epileptic patients. Blood and saliva samples were taken simultaneously at 0 hours and 24 hours of CBZ dosing from 31 epileptic patients, receiving CBZ monotherapy for three or more months. Levels of CBZ in both these fluids were measured by high performance liquid chromatography. Strong and highly significant correlation was found between serum and salivary CBZ concentration (r = 0.659, p<0.001). Estimation of CBZ level in saliva is thus a practicable, valid and convenient method of TDM in epileptic patients.

How to cite this article:
Vasudev A, Tripathi K D, Puri V. Correlation of serum and salivary carbamazepine concentration in epileptic patients : implications for therapeutic drug monitoring. Neurol India 2002;50:60


How to cite this URL:
Vasudev A, Tripathi K D, Puri V. Correlation of serum and salivary carbamazepine concentration in epileptic patients : implications for therapeutic drug monitoring. Neurol India [serial online] 2002 [cited 2019 Dec 9];50:60. Available from: http://www.neurologyindia.com/text.asp?2002/50/1/60/1361




      Introduction Top

Therapeutic drug monitoring (TDM) of anti-epileptic drugs has been found to be very useful in optimizing seizure control and in avoiding and detecting drug toxicity.[1] Carbamazepine (CBZ) is a first line drug used in a variety of seizure disorders including partial seizures and generalized tonic clonic seizures.[2],[3],[4]

Blood collection for TDM has got its antecedent problems. As an alternative, saliva has been used previously for measurement of drug levels. The major advantage of saliva is that it can be obtained noninvasively. Other advantages include collection of sample at home, patient preference especially in pediatric and geriatric population and low cost.[5] Many studies have shown a good correlation between serum and salivary levels of phenytoin, phenobarbital and CBZ.[6] However, TDM of CBZ in saliva is not routinely practiced, and there are no reports of such monitoring from India. The present study has been
carried out to examine the feasibility and validity of salivary CBZ measurements for routine therapeutic drug monitoring in epileptic patients.


      Material and methods Top

The study was conducted in 31 consecutive epileptic patients of either sex, aged 15-60 years, attending the Neurology clinic of GB Pant Hospital, New Delhi. All patients were receiving CBZ monotherapy (dose range 200-1300 mg/day) for the past 3 or more months. Only those patients whose baseline liver and kidney function tests were within normal range, who had no symptomatic cause of epilepsy, and who had no history of intake of other drugs that could interfere with CBZ metabolism (macrolide antibiotics, isoniazid, metronidazole, acetazolamide, antidepressants, diltiazem, cimetidine, danazol and propoxyphene) over the preceding three months, were included. Patients whose compliance was suspect, pregnant or lactating women, patients with an overt endocrine disorder and those with a history suggestive of organic brain syndrome were excluded.
On the day of the study, patients were admitted to the Neurology ward. Blood and salivary samples were collected and the total daily dose of CBZ was administered on an empty stomach. Another set of blood and salivary samples was taken after 24 hours. Serum was separated by centrifugation. Saliva was also centrifuged to obtain the clear supernatant. Both serum and salivary samples were stored at -20oC until assayed by HPLC, according to the method of Asteir and Maury,[7] with slight modification (flow rate 0.6 ml/min instead of 1 ml/ min; detection wave length 254 nm instead of 288 nm) and using nitrazepam as internal standard. The variability in CBZ assay between day and within day, was found to be less than 5%.


      Results Top

Cabamazepine concentration was measured in 62 pairs of concurrently obtained serum and salivary samples [Table I]. The mean (SD) serum CBZ levels at 0 hours was 2.391.37g/ml, and at 24 hours it was 2.161.25 g/ml. The above values did not differ from each other significantly (p=0.504). Similarly, the CBZ levels in saliva at 0 hours and at 24 hours had a mean of 1.010.79 g/ml and 0.830.78 g/ml respectively. These two values also did not differ significantly from each other (p=0.35). The mean pooled serum concentration of CBZ was 2.271.31 g/ml and the mean salivary CBZ concentration was 0.920.79 g/ml. As such, the overall ratio of salivary to serum CBZ concentration was 0.40.
A scatter plot of the serum versus salivary CBZ levels [Figure 1] revealed a good linear relationship (correlation coefficient, r = 0.659, p<0.001). The slope of the regression analysis was found to be 0.397, which is close to the ratio of salivary to serum CBZ concentration. The regression analysis can be represented by the following : y = 0.397 x + 0.0178; where y is the salivary concentration and x is the serum concentration of CBZ.



      Discussion Top

Blood CBZ concentrations are a useful guide in evaluating compliance and in adjusting dosage and preventing toxicity.[5] In the present study of 31 epileptic patients, all had serum CBZ concentrations within the therapeutic range of CBZ, but only 16 were fully controlled, while 15 patients were only partially controlled or not controlled at all. The corresponding salivary CBZ concentrations had a good correlation with the serum CBZ concentrations (r = 0.659, p<0.001). It was observed that one particular pair of values did not conform to the usual pattern; salivary CBZ concentration 3.27 g/ml and serum CBZ concentration 1.2 g/ml (marked with a star in Fig. 1). The correlation coefficient improved to r = 0.76 on deleting this value. Other authors have also documented good correlation values of 0.991[8] and 0.84.[9],[5]
The concentration of a drug in saliva may reflect the free concentration (unbound fraction) in serum. This fraction crosses all biological membranes, reaches the effector site and should correlate better with the effect than the total serum concentration.[5] Therefore, it seems that measurement of the unbound concentration of CBZ would lead to a better correlation with seizure control. CBZ is bound to plasma proteins to the extent of 70%. The unbound fraction can be measured by equilibrium dialysis and ultrafiltration, but these are difficult, time consuming and expensive, and therefore not routinely employed. Further, only total (bound and unbound) serum CBZ values have been reported in defining the therapeutic range of CBZ. Salivary drug measurement offers an inexpensive and an easy technique to measure drug concentrations. The high correlation coefficient between salivary and serum CBZ concentrations imply that measurement of CBZ levels in saliva offers a convenient and reproducible method of assessing the concentration of CBZ in serum.
Unstimulated, as well as stimulated salivary secretion has been used for TDM of CBZ. While Gorodischer et al[10] found citric acid stimulated saliva to be a convenient method for TDM in infants and children, Paxton et al[9] observed that whole salivary and uncontaminated parotid salivary CBZ concentrations to be similar and independent of volume of fluid, pH of saliva and degree of stimulation. As such, unstimulated salivary sampling was used in the present study. It was found that collection of saliva in a universal container does not require any special equipment. By simple spitting, an adequate amount of saliva can be collected for drug level measurement. None of our patients expressed any hesitancy or difficulty in bringing out saliva. Thus, it is suggested that saliva can be used routinely in our set up for TDM of CBZ.

 

     References Top

1.Choonara IA, Rane A : Therapeutic drug monitoring of anticonvulsants: state of the art. Clin Pharmacokinet 1990;18 : 318-328.   Back to cited text no. 1    
2.Bialer M, Levy RH, Perucca E : Does carbamazepine have a narrow therapeutic plasma concentration range. Ther Drug Monit 1998; 20 : 56-59.   Back to cited text no. 2    
3.Mc Namara JO : Drugs effective in the therapy of epilepsies. In : Goodman and Gilman's the pharmacological basis of therapeutics. Molinoff PB, Ruddon RN (eds). Mc Graw Hill, 9th edition, 1996; 461-485.   Back to cited text no. 3    
4.Mattson RH, Cramer JA, Collins JF et al : Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalised tonic clonic seizures. N Eng J Med 1985; 313 : 145-151.   Back to cited text no. 4    
5.Gorodischer R, Burtin P, Verjee Z et al : Is saliva suitable for therapeutic drug monitoring of anticonvulsants in children: an evaluation in the routine clinical setting. Ther Drug Monit 1997; 19 : 637-642.   Back to cited text no. 5    
6.Schramm W, Smith RH : An ultrafiltrate of saliva collected in situ as a biological sample for diagnostic evaluation. Clin Chem 1991; 37 : 114-115.   Back to cited text no. 6    
7.Asteir A, Maury M : Simultaneous, rapid high performance liquid chromatographic microanalysis of plasma carbamazepine and its 10, 11 epoxide metabolite. J Chromatogr 1979; 164 : 235-240.   Back to cited text no. 7    
8.Westernberg, Eppo Kleion, Oei TT : Kinetics of carbamazepine and carbamazepine epoxide determined by use of plasma and saliva. Clin Pharmacol Ther1978; 23 : 320-328.   Back to cited text no. 8    
9.Paxton W, Roger A. Donald : Concentrations and kinetics of carbamazepine in whole saliva, parotid saliva, serum ultrafiltrate and serum. Clin Pharmacol Ther 1980;28 : 695-702.   Back to cited text no. 9    
10.Gorodischer R, Burtin P, Verjee Z et al : Is saliva suitable for therapeutic monitoring of anticonvulsants in children: an evaluation in the routine clinical setting. Ther Drug Monit 1997; 19 : 637-642.   Back to cited text no. 10    

 

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