Kinetics of carbamazepine and carbamazepine-epoxide, determined by use of plasma and saliva The concentration-time curves of carbamazepine (CBZ) and its metabolite (carbamazepine-JO,/ I-epoxide; CBZ-epoxide) were determined in patients undergoing long-term antiepileptic drug treatment with the use of plasma and saliva data. Plasma and saliva samples were assayed concurrently for each patient by liquid chromatography. There was excellent linear correlation between CBZ levels in saliva and plasma (r = 0.991, p < 0.001) over a large concentration range. The saliva/plasma ratio for CBZ concentration was 0.26 ± 0.01 (SD). Since CBZ binding to plasma proteins is in the order of 76%, saliva CBZ concentration seems to reflect the unbound fraction of the drug in plasma. CBZ-epoxide has not been detected in saliva. The pharmacokinetic parameters of CBZ-epoxide were determined in 6 patients. The pharmacokinetic parameters of CBZ obtained from saliva concentrations were in excellent agreement with those obtained from plasma concentrations. Thus, CBZ determination in saliva is convenient for controlling blood levels in patients as well as for studying pharmacokinetics. The half-life, the relative body clearance of CBZ, and the metabolite concentration during steady-state, expressed as percent the parent compound, appear to be significantly different in patients on single and combined drug therapy.
Herman G. M. Westen berg, Eppo van der Kleijn, Ph.D., Tiauw T. Oei, M.D., and Rokus A. de Zeeuw, Ph.D. Groningen and Vught, The Netherlands Laboratory for Pharmaceutical and Analytical Chemistry, State University, Groningen, Department of Clinical Pharmacy, University of Nijmegen, and Psychiatrische Instituten van de Godshuizen, Vught
Carbamazepine (Tegretol) has been used successfully in the treatment of patients with epilepsy and trigeminal neuralgia. The drug has been shown to be as effective as phenytoin (DPH) pr phenobarbital (PB) in the treatment of grand mal and complex partial seizure. 4 , 14,31 In trigeminal neuralgia, carbamazepine (CBZ) apReceived for publication June 10, 1977. Accepted for pUblication Oct. 20, 1977. Reprint requests to: H. G. M. Westenberg, Laboratory for Pharmaceutical and Analytical Chemistry, Deusinglaan 2, Groningen, The Netherlands.
320
pears to be the drug of choice. 2 • 6 Schneider9 has suggested that there is a relationship between the serum level of CBZ and seizure control. Adjustment of the dosage, based on the determination of blood levels, is therefore considered very important. Knowledge of kinetics is likewise of great importance. Carbamazepine-lO, ll-epoxide (CBZ-epoxide) is one of the main metabolites of CBZ in man. lo In rats, this epoxide metabolite, has been found to display anticonvulsi ve activity, II. 12 although, to our knowledge, this activity has
0009-9236178/0323-0320$00.90/0 © 1978 The C. V. Mosby Co.
Volume 23 Number 3
Carbamazepine kinetics
321
Table I. Dosage schedule of CBZ, comedications, and assay schedule of the patients included in this study Assay schedule Patient Weight Height (em) DPH No. Sex (kg) I
F
2 3 4 5 6 7
F F F F F
8
F
9
10
M
M M
57 54 51 72 63 62
166 170 154 167 171 167 160
47 64 63
147 175 178
72
Comedication
IPB I
x x x
x x x
x
x
x
Other comedication
Fluphenazine Perphenazine, orphenadrine Perphenazine Diazepam Fluphenazine None Fluphenazine,orphenadrine Fluspirilenet None None
Plasma Daily dose Saliva CBZ (mg) CBZ CBZ-epoxide (CBZ)
1
x 100 x x 100 x x 200 x x 200 x x 200 x x 200 x x 400, x I x 100 3 x 200 x 3 x 200 x 3 x 200 x 3 3 3 3 3 3 3
x x x x
x x x x x* x* x*
x x
CBZ: carbamazepine; DPH: diphenylhydantoin; PB: phenobarbital. ·Only during steady-state. t Not available in the United States.
never been confirmed in man. It may be possible that both CBZ and its epoxide metabolite contribute to the therapeutic effect. It is therefore important to measure the plasma levels of both. Investigations dealing with the disposition of CBZ in man have recently received considerable attention 9 , 22, 24, 26 but comparatively little information is available on the pharmacokinetics of CBZ and its main metabolite in patients undergoing long-term treatment. It has also been shown that pharmacokinetic parameters, obtained from single-dose experiments in normal volunteers, cannot be applied directly to patients receiving CBZ chronically, either alone or in combination with other drugs. 9 , 26, 30 Patient compliance is another factor that should always be considered. 7 The aim of our investigation was to establish the pharmacokinetics of CBZ with and without concomitant administration of other drugs. Since blood samples must be drawn by skilled personnel and problems may arise when serial samples are needed, e.g., for pharmacokinetic studies, a more accessible body fluid is often a great convenience, since a number of drugs appear in significant concentrations in the saliva, provided there is a fixed and linear relationship between the plasma and the saliva concentrations, saliva levels may offer a safe, convenient, and noninvasive al-
temative. Investigations dealing with this relationship have recently received considerable attention. 3 , 13,21,28,32,35 Therefore, it was also decided to assess whether there is such a relationship in order to explore the usefulness of measuring CBZ and CBZ-epoxide in saliva for pharmacokinetic studies as well as for monitoring drug levels. Materials and methods
The subjects were 10 patients (3 men and 7 women) aged 17 to 63 yr. They were treated with CBZ for at least 2 mo (range, 2 mo to 8 yr). Most of them received other drugs as well (Table I). During this investigation most patients continued on normal medication schedules, except for CBZ. CBZ was administered at 8:00 A.M., 4:00 P.M., and 10:00 P.M. during 2 days in the same daily dose as subjects usually took. Blood samples were taken at 1, 3, 5, and 8 hr after the first dose of each day. Following that all patients stopped taking CBZ for at least 60 hr. Blood samples were taken at regular intervals during this period to determine plasma half-life (t'h). In some patients (Table I), saliva samples were collected at the same time as the blood samples. Venous blood was collected in heparinized tubes, and plasma was separated by centrifugation. Mixed saliva samples (0.5 to 2 m!) were collected over a 3-min interval, and
322
Westenberg et al.
Clin. Pharmacol. Ther. March 1978
concentration ( mg/l ; log scale) - - - - - - - - - 10 subject 1
5L
........ ' V -.. ""'"
2
....,.,............... ."',,-
cbz plasma
~
0·5
, ..
.'
..
"
,
.....................................
~. bz
~
0·2 cbz -epox i de plasma
0·1
•
0·05
o
r
20
r r
1
40
r
60
80
" 100 time (h)
dose 100 mg
Fig. 1. Semilogarithmic concentration·time curves of CBZ in plasma (0) and saliva (x) and of CBZ·epoxide in plasma (e) of Subject 1. Steady·state concentrations were measured between two doses during the first 2 days. CBZ was administered as indicated.
salivation was stimulated, if necessary, by chewing on a piece of Parafilm. Plasma and saliva samples were kept frozen at - 20° C until required for analysis. Assay procedure. CBZ and CBZ-epoxide concentrations in plasma were analyzed in duplicate by liquid chromatography according to Westenberg and De Zeeuw. 36 Saliva samples were centrifugated to separate mucus and cellular debris and were analyzed by an essentially identical procedure. The coefficient of variation of the method did not exceed 2% for CBZ and 4% to 5% for CBZ-epoxide, within the concentration range encountered in practice. CBZ can be analyzed in both plasma and saliva down to 5 ng/ml, and the lower limit of detection for CBZ-epoxide is 25 ng/ml. Results
The dosage schedule of CBZ, the comedic ations, and the assay schedule of the individual patients are listed in Table I. The concentration-time curves of CBZ in plasma and saliva and of CBZ-epoxide in plasma for Patient
1, a representative example, is depicted in Fig. 1, which shows that there is a close relationship between CBZ concentrations in plasma and saliva under steady-state conditions. CBZepoxide could not be detected in saliva due to the limits of the method used, nor could other metabolites such as 2-, and 3-hydroxyCBZ, 10, ll-transdihydroxy·dihydro-CBZ, and 9-hydroxymethyl-IO-carbamoyl-acridan be detected. A more specific procedure* that was adapted to these components showed that these metabolites are present in plasma in trace amounts. After interrupting CBZ treatment, the decline of the CBZ concentration in plasma and saliva and the decline of the CBZ-epoxide concentration in plasma were followed to estimate the biological tVzs. CBZ was eliminated from both fluids in a monoexponential and parallel fashion. The parallelism between the CBZ concentration in plasma and saliva is demonstrated by the essentially identical tlhs in both fluids (Ta*Westenberg. H. O. M., et al.: Results to be published.
Volume 23 Number 3
Carbamazepine kinetics
ble II). A strong correlation was found between the concentrations of CBZ in plasma and saliva (r = 0.991, P < 0.001), the saliva/plasma ratio being 0.26 ± 0.01 (SD), calculated by averaging all ratios (n = 85) of 7 patients during the entire experimental period (Fig. 2). The saliva/plasma ratios of the individual patients are summarized in Table II. The ratios appeared to be constant over a large concentration range (0.2 to 8.0 ILg/ml). Table II is a summary of the most important pharmacokinetic parameters of CBZ obtained from plasma and saliva data in patients chronically treated with CBZ. The mean plasma level of the patients was found to be 5.7 ± 1.1 (SD) ILg/ml, at a mean daily dose of 10.2 ± 4.5 mg/kg body weight. The t%s and the elimination rate constants (kel) were calculated with the use of log-linear regression analysis of the data obtained in the period during which CBZ medication was interrupted. The monophasic exponential decay of the concentrations suggested that the open one-compartment model could be applied. Steady-state concentrations with the use of the mean concentration of two subsequent days and dosage per kg body weight were used to calculate the relative total body clearance (K') and the relative apparent volume of distribution (V') by means of Equation 1 by Wagner and associates. 34 F· Dose Css = K' . T.W
(I)
in which K' = V' . kel, css is the mean steady-state concentration, kel is the elimination rate constant, F is the fraction of the dose reaching the systemic circulation (bioavailability), T is the dosage interval, and W is the body weight of the individual patient. The bioavailability was assumed to be 100% (F = 1). The kinetic data of CBZ-epoxide, the major metabolite of CBZ is shown in Table III. The plasma concentrations of CBZ-epoxide were much lower than those of CBZ. The mean steady-state level of CBZ-epoxide in plasma varied from 0.31 to 1.0 ILg/ml. The plasma concentrations of CBZ-epoxide accounted for about 5% to 20% of CBZ itself. The apparent plasma tlhs of CBZ-epoxide, as calculated from the tangent of the posttreatment curves, are
323
plasma carbamazepine (mg/l) - - - - - - - - . , 10
8
6
4
n=85
0·5
1.5 2·0 1·0 2·5 saliva carbamazepine (mgll)
Fig. 2. Correlation between the saliva and plasma concentrations of CBZ in 7 subjects.
summarized in Table III. The real t% of CBZepoxide cannot be calculated from the posttreatment curve, since the slopes of the descending part of the semilogarithmic plasma curves of both drug and metabolite were parallel. Considering a catenary infusion model as described by Wagner,33 in which CBZ is supposedly eliminated completely by metabolism into CBZ-epoxide, and assuming equal volumes of distribution for both parent compound and metabolite, the t% of the epoxide metabolite can be estimated with the aid of Equation 2.20 C I = kel2 = t%(l) kell t%(2) CI
(2)
where C I and C 2 are the mean plasma steadystate concentrations and kell and kel2 are the elimination rate constants of CBZ and CBZepoxide, respectively. In order to investigate the influence of DPH and phenobarbital (PB) comedication on the pharrnacokinetic behavior of CBZ, the patients were divided into two different groups (Table IV). Group A represents the results (mean values and standard deviations) of data obtained from patients treated with CBZ alone, whereas the results from patients receiving CBZ in combination with DPH or PB or both are given in group B. The mean plasma t% (p < 0.05) and the mean relative body clearance (p < 0.02) in group A appeared to be different from
Westenberg et al.
324
Clin. Pharmacol. Ther. March 1978
Table II. Pharmacokinetic parameters of CBZ in patients after long-term treatment as determined from plasma and saliva Patient No.
Dose (mg/kg)
tl/2 (hr) Plasma
10
9.5
14.1 ±0.2 20.9 ±0.6 10.7 ±0.2 11.3 ±0.3 11.2 ±0.6 14.3 ±0.8 10.2 ±0.5 9.7 ±0.4 16.0 ±0.8 26.1 ± 1.9
Mean SO n
10.2 ±4.5 10
14.5 ±5.3 10
5.3 2
5.6
3
11.8
4
8.3
5
9.5
6
8.3
7
21.0
8
13.0
9
9.4
I Saliva 14.3 ±0.4 19.5 ±0.7 10.3 ±0.2 11.9 ±0.3
14.0 ±4.0 4
kel (hr- I ) Plasma
I
Saliva
V' (L . kg-I)
K' (L . kg-I. hr- I)
Plasma
I Saliva
Plasma
I
Saliva
0.049
0.049
0.96
3.8
0.047
0.187
0.033
0.036
1.32
4.8
0.044
0.171
0.065
0.067
1.66
4.8
0.108
0.377
0.062
0.058
1.14
5.5
0.070
0.278
0.062
1.37
4.8
0.085
0.333
0.049
1.14
0.056
0.231
0.068
2.00
0.136
0.502
0.072
1.47
0.106
0.043
1.17
0.051
0.027 0.053 ±0.015 10
2.07 0.053 ±0.013 4
1.43 ±0.37 10
0.055 4.71 ±0.67 4
0.076 ±0.032 10
0.295 ±0.116 7
The values indicate mean ± SD. The number of determinations is given in parentheses. t'h: half-life; kel: elimination rate constant; V': relative volume of distribution; K': relative body clearance; C,,: mean steady-state concentration.
the corresponding values in group B. The relative volume of distribution in group A was not found to be different from that in group B (p > 0.05). The ratio between the CBZepoxide and the CBZ concentrations in group A was found to be higher than the ratio in group B. It should be emphasized, however, that the latter finding was obtained with a relatively small number of patients, and that its stati
Herman G. M. Westen berg, Eppo van der Kleijn, Ph.D., Tiauw T. Oei, M.D., and Rokus A. de Zeeuw, Ph.D. Groningen and Vught, The Netherlands Laboratory for Pharmaceutical and Analytical Chemistry, State University, Groningen, Department of Clinical Pharmacy, University of Nijmegen, and Psychiatrische Instituten van de Godshuizen, Vught
Carbamazepine (Tegretol) has been used successfully in the treatment of patients with epilepsy and trigeminal neuralgia. The drug has been shown to be as effective as phenytoin (DPH) pr phenobarbital (PB) in the treatment of grand mal and complex partial seizure. 4 , 14,31 In trigeminal neuralgia, carbamazepine (CBZ) apReceived for publication June 10, 1977. Accepted for pUblication Oct. 20, 1977. Reprint requests to: H. G. M. Westenberg, Laboratory for Pharmaceutical and Analytical Chemistry, Deusinglaan 2, Groningen, The Netherlands.
320
pears to be the drug of choice. 2 • 6 Schneider9 has suggested that there is a relationship between the serum level of CBZ and seizure control. Adjustment of the dosage, based on the determination of blood levels, is therefore considered very important. Knowledge of kinetics is likewise of great importance. Carbamazepine-lO, ll-epoxide (CBZ-epoxide) is one of the main metabolites of CBZ in man. lo In rats, this epoxide metabolite, has been found to display anticonvulsi ve activity, II. 12 although, to our knowledge, this activity has
0009-9236178/0323-0320$00.90/0 © 1978 The C. V. Mosby Co.
Volume 23 Number 3
Carbamazepine kinetics
321
Table I. Dosage schedule of CBZ, comedications, and assay schedule of the patients included in this study Assay schedule Patient Weight Height (em) DPH No. Sex (kg) I
F
2 3 4 5 6 7
F F F F F
8
F
9
10
M
M M
57 54 51 72 63 62
166 170 154 167 171 167 160
47 64 63
147 175 178
72
Comedication
IPB I
x x x
x x x
x
x
x
Other comedication
Fluphenazine Perphenazine, orphenadrine Perphenazine Diazepam Fluphenazine None Fluphenazine,orphenadrine Fluspirilenet None None
Plasma Daily dose Saliva CBZ (mg) CBZ CBZ-epoxide (CBZ)
1
x 100 x x 100 x x 200 x x 200 x x 200 x x 200 x x 400, x I x 100 3 x 200 x 3 x 200 x 3 x 200 x 3 3 3 3 3 3 3
x x x x
x x x x x* x* x*
x x
CBZ: carbamazepine; DPH: diphenylhydantoin; PB: phenobarbital. ·Only during steady-state. t Not available in the United States.
never been confirmed in man. It may be possible that both CBZ and its epoxide metabolite contribute to the therapeutic effect. It is therefore important to measure the plasma levels of both. Investigations dealing with the disposition of CBZ in man have recently received considerable attention 9 , 22, 24, 26 but comparatively little information is available on the pharmacokinetics of CBZ and its main metabolite in patients undergoing long-term treatment. It has also been shown that pharmacokinetic parameters, obtained from single-dose experiments in normal volunteers, cannot be applied directly to patients receiving CBZ chronically, either alone or in combination with other drugs. 9 , 26, 30 Patient compliance is another factor that should always be considered. 7 The aim of our investigation was to establish the pharmacokinetics of CBZ with and without concomitant administration of other drugs. Since blood samples must be drawn by skilled personnel and problems may arise when serial samples are needed, e.g., for pharmacokinetic studies, a more accessible body fluid is often a great convenience, since a number of drugs appear in significant concentrations in the saliva, provided there is a fixed and linear relationship between the plasma and the saliva concentrations, saliva levels may offer a safe, convenient, and noninvasive al-
temative. Investigations dealing with this relationship have recently received considerable attention. 3 , 13,21,28,32,35 Therefore, it was also decided to assess whether there is such a relationship in order to explore the usefulness of measuring CBZ and CBZ-epoxide in saliva for pharmacokinetic studies as well as for monitoring drug levels. Materials and methods
The subjects were 10 patients (3 men and 7 women) aged 17 to 63 yr. They were treated with CBZ for at least 2 mo (range, 2 mo to 8 yr). Most of them received other drugs as well (Table I). During this investigation most patients continued on normal medication schedules, except for CBZ. CBZ was administered at 8:00 A.M., 4:00 P.M., and 10:00 P.M. during 2 days in the same daily dose as subjects usually took. Blood samples were taken at 1, 3, 5, and 8 hr after the first dose of each day. Following that all patients stopped taking CBZ for at least 60 hr. Blood samples were taken at regular intervals during this period to determine plasma half-life (t'h). In some patients (Table I), saliva samples were collected at the same time as the blood samples. Venous blood was collected in heparinized tubes, and plasma was separated by centrifugation. Mixed saliva samples (0.5 to 2 m!) were collected over a 3-min interval, and
322
Westenberg et al.
Clin. Pharmacol. Ther. March 1978
concentration ( mg/l ; log scale) - - - - - - - - - 10 subject 1
5L
........ ' V -.. ""'"
2
....,.,............... ."',,-
cbz plasma
~
0·5
, ..
.'
..
"
,
.....................................
~. bz
~
0·2 cbz -epox i de plasma
0·1
•
0·05
o
r
20
r r
1
40
r
60
80
" 100 time (h)
dose 100 mg
Fig. 1. Semilogarithmic concentration·time curves of CBZ in plasma (0) and saliva (x) and of CBZ·epoxide in plasma (e) of Subject 1. Steady·state concentrations were measured between two doses during the first 2 days. CBZ was administered as indicated.
salivation was stimulated, if necessary, by chewing on a piece of Parafilm. Plasma and saliva samples were kept frozen at - 20° C until required for analysis. Assay procedure. CBZ and CBZ-epoxide concentrations in plasma were analyzed in duplicate by liquid chromatography according to Westenberg and De Zeeuw. 36 Saliva samples were centrifugated to separate mucus and cellular debris and were analyzed by an essentially identical procedure. The coefficient of variation of the method did not exceed 2% for CBZ and 4% to 5% for CBZ-epoxide, within the concentration range encountered in practice. CBZ can be analyzed in both plasma and saliva down to 5 ng/ml, and the lower limit of detection for CBZ-epoxide is 25 ng/ml. Results
The dosage schedule of CBZ, the comedic ations, and the assay schedule of the individual patients are listed in Table I. The concentration-time curves of CBZ in plasma and saliva and of CBZ-epoxide in plasma for Patient
1, a representative example, is depicted in Fig. 1, which shows that there is a close relationship between CBZ concentrations in plasma and saliva under steady-state conditions. CBZepoxide could not be detected in saliva due to the limits of the method used, nor could other metabolites such as 2-, and 3-hydroxyCBZ, 10, ll-transdihydroxy·dihydro-CBZ, and 9-hydroxymethyl-IO-carbamoyl-acridan be detected. A more specific procedure* that was adapted to these components showed that these metabolites are present in plasma in trace amounts. After interrupting CBZ treatment, the decline of the CBZ concentration in plasma and saliva and the decline of the CBZ-epoxide concentration in plasma were followed to estimate the biological tVzs. CBZ was eliminated from both fluids in a monoexponential and parallel fashion. The parallelism between the CBZ concentration in plasma and saliva is demonstrated by the essentially identical tlhs in both fluids (Ta*Westenberg. H. O. M., et al.: Results to be published.
Volume 23 Number 3
Carbamazepine kinetics
ble II). A strong correlation was found between the concentrations of CBZ in plasma and saliva (r = 0.991, P < 0.001), the saliva/plasma ratio being 0.26 ± 0.01 (SD), calculated by averaging all ratios (n = 85) of 7 patients during the entire experimental period (Fig. 2). The saliva/plasma ratios of the individual patients are summarized in Table II. The ratios appeared to be constant over a large concentration range (0.2 to 8.0 ILg/ml). Table II is a summary of the most important pharmacokinetic parameters of CBZ obtained from plasma and saliva data in patients chronically treated with CBZ. The mean plasma level of the patients was found to be 5.7 ± 1.1 (SD) ILg/ml, at a mean daily dose of 10.2 ± 4.5 mg/kg body weight. The t%s and the elimination rate constants (kel) were calculated with the use of log-linear regression analysis of the data obtained in the period during which CBZ medication was interrupted. The monophasic exponential decay of the concentrations suggested that the open one-compartment model could be applied. Steady-state concentrations with the use of the mean concentration of two subsequent days and dosage per kg body weight were used to calculate the relative total body clearance (K') and the relative apparent volume of distribution (V') by means of Equation 1 by Wagner and associates. 34 F· Dose Css = K' . T.W
(I)
in which K' = V' . kel, css is the mean steady-state concentration, kel is the elimination rate constant, F is the fraction of the dose reaching the systemic circulation (bioavailability), T is the dosage interval, and W is the body weight of the individual patient. The bioavailability was assumed to be 100% (F = 1). The kinetic data of CBZ-epoxide, the major metabolite of CBZ is shown in Table III. The plasma concentrations of CBZ-epoxide were much lower than those of CBZ. The mean steady-state level of CBZ-epoxide in plasma varied from 0.31 to 1.0 ILg/ml. The plasma concentrations of CBZ-epoxide accounted for about 5% to 20% of CBZ itself. The apparent plasma tlhs of CBZ-epoxide, as calculated from the tangent of the posttreatment curves, are
323
plasma carbamazepine (mg/l) - - - - - - - - . , 10
8
6
4
n=85
0·5
1.5 2·0 1·0 2·5 saliva carbamazepine (mgll)
Fig. 2. Correlation between the saliva and plasma concentrations of CBZ in 7 subjects.
summarized in Table III. The real t% of CBZepoxide cannot be calculated from the posttreatment curve, since the slopes of the descending part of the semilogarithmic plasma curves of both drug and metabolite were parallel. Considering a catenary infusion model as described by Wagner,33 in which CBZ is supposedly eliminated completely by metabolism into CBZ-epoxide, and assuming equal volumes of distribution for both parent compound and metabolite, the t% of the epoxide metabolite can be estimated with the aid of Equation 2.20 C I = kel2 = t%(l) kell t%(2) CI
(2)
where C I and C 2 are the mean plasma steadystate concentrations and kell and kel2 are the elimination rate constants of CBZ and CBZepoxide, respectively. In order to investigate the influence of DPH and phenobarbital (PB) comedication on the pharrnacokinetic behavior of CBZ, the patients were divided into two different groups (Table IV). Group A represents the results (mean values and standard deviations) of data obtained from patients treated with CBZ alone, whereas the results from patients receiving CBZ in combination with DPH or PB or both are given in group B. The mean plasma t% (p < 0.05) and the mean relative body clearance (p < 0.02) in group A appeared to be different from
Westenberg et al.
324
Clin. Pharmacol. Ther. March 1978
Table II. Pharmacokinetic parameters of CBZ in patients after long-term treatment as determined from plasma and saliva Patient No.
Dose (mg/kg)
tl/2 (hr) Plasma
10
9.5
14.1 ±0.2 20.9 ±0.6 10.7 ±0.2 11.3 ±0.3 11.2 ±0.6 14.3 ±0.8 10.2 ±0.5 9.7 ±0.4 16.0 ±0.8 26.1 ± 1.9
Mean SO n
10.2 ±4.5 10
14.5 ±5.3 10
5.3 2
5.6
3
11.8
4
8.3
5
9.5
6
8.3
7
21.0
8
13.0
9
9.4
I Saliva 14.3 ±0.4 19.5 ±0.7 10.3 ±0.2 11.9 ±0.3
14.0 ±4.0 4
kel (hr- I ) Plasma
I
Saliva
V' (L . kg-I)
K' (L . kg-I. hr- I)
Plasma
I Saliva
Plasma
I
Saliva
0.049
0.049
0.96
3.8
0.047
0.187
0.033
0.036
1.32
4.8
0.044
0.171
0.065
0.067
1.66
4.8
0.108
0.377
0.062
0.058
1.14
5.5
0.070
0.278
0.062
1.37
4.8
0.085
0.333
0.049
1.14
0.056
0.231
0.068
2.00
0.136
0.502
0.072
1.47
0.106
0.043
1.17
0.051
0.027 0.053 ±0.015 10
2.07 0.053 ±0.013 4
1.43 ±0.37 10
0.055 4.71 ±0.67 4
0.076 ±0.032 10
0.295 ±0.116 7
The values indicate mean ± SD. The number of determinations is given in parentheses. t'h: half-life; kel: elimination rate constant; V': relative volume of distribution; K': relative body clearance; C,,: mean steady-state concentration.
the corresponding values in group B. The relative volume of distribution in group A was not found to be different from that in group B (p > 0.05). The ratio between the CBZepoxide and the CBZ concentrations in group A was found to be higher than the ratio in group B. It should be emphasized, however, that the latter finding was obtained with a relatively small number of patients, and that its stati
