Europ.J.clin.Pharmacol. 9, 417-421 (1976) © by Springer-Verlag 1976
Plasma Levels of Carbamazepine and Carbamazepine-10,11-epoxide during Treatment of Epilepsy M. Eichelbaum*, L. Bertilsson**, L. Lund, L. Palrn6r and F. Sj6qvist Departments of Clinical Pharmacology, Huddinge Hospital, Neurology, Karolinska Hospital and Toxicology, Karolinska Institute, Stockholm, Sweden
Received: May 5, 1975, accepted: September 10, 1975
Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 ± 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 ± 2.5 ~g/ml and 1.10 ± 0.42 ug/ml, respectively. A significant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p O . 0 5 )
Table
2. N u m b e r
in c o m b i n a t i o n
of s e i z u r e s with
and plasma
I
I
I
I
l
I
I
I
2
3
4
5
6
7
8
9 10 11 12 1 3 1 4 15
a
I
I
!
I
I
~ g carbamazepine/mtplasma
Fig. 2. R e l a t i o n s h i p b e t w e e n p l a s m a c o n c e n t r a t i o n of c a r b a m a z e p i n e a n d its e p o x i d e m e t a b o l i t e in e p i l e p t i c p a t i e n t s (r = 0.64; p < O . O 0 1 )
concentrations
of d r u g s
during
treatment
with
DPH
alone
partial seizures
6 months
mean DPH plasma concentration
Treatment with DPH and carbamazepine Total number of grand mal partial seizures seizures
ug/ml
during 6 months
mean DPH plasma concentration pg/ml
range of the p l a s m a concentrations of carbamazepine
~g/ml
change in partial seizure between the two periods iin %)
30
16.O
-
27
16.4
4.8-7.9
-10
L.B.
0
8
13.0
I
i0
14.2
3.9-5.2
+25
C.E.
-
6
15.3
2
16.8
4.9
-67
H.J.
-
42
15.O
M.K.
-
22
]4.2
H.L.
2
64
B.L.
-
42
K.K.
4
120
15.O
G.L.
-
35
E.O.
2
12
E.R.
-
5
15.O
C.R.
1
8
15.2
P.W.
3
140
20.2
3
R.B.
and
carbamazepine
Treatment with DPH during Total number of grand mal seizures
I
1
47
17.2
3.5-6.9
+I0
-
16
16.O
3.2-4.5
-30
18.O
i
59
17.2
4.3-6. i
-i0
16.O
-
30
16.8
4.9
-30
5
132
15.2
5.0-8.2
+i0
12.0
-
52
13.4
2.9-6.5
+50
15.2
2
11
16.0
2.9-3.0
0
-
2
14.2
5.1-5.5
-60
0
17
15.9
I .4-3.9
+iOO
125
19.8
4.5-6.7
-IO
420
mass fragmentography according to Palmer et al. (1973). The correlation between the two methods of r = 0.99 has previously been reported (Eichelbaum and Bertilsson, 1974). Plasma levels quoted in this report were obtained by liquid chromatography.
RESULTS AND DISCUSSION The prescribed doses of carbamazepine and DPH and the concentrations of DPH, carbamazepine, carbamazepine-10,11epoxide and the ratio between the latter two for each of the 25 patients studied are shown in Table I. The mean concentrations of carbamazepine and its epoxide were 5.4 ± 2.5 pg/ml and 1.10 ± 0.42 pg/ml, respectively (n = 25). The m e a n daily dose of carbamazepine was 12.5 ± 3.3 mg/kg body weight (n = 25). In Fig. I the prescribed daily dose of carbamazepine has been plotted against the plasma level of carbamazepine. Regression analysis showed no significant correlation (r = 0.19) between them, implying that the plasma concentration achieved cannot readily be predicted from the prescribed dose. The relationship between the concentration of carbamazepine and its epoxide in plasma (r = 0.64) is shown in Fig. 2. This correlation indicates that change in the plasma level of carbamazepine will usually result in a proportional change in the concentration of the epoxide. However, there was interindividual variation in the ratio between parent compound and metabolite, the latter reaching levels between 15 and 55% of the former. In two patients the concentration of carbamazepine and its epoxide were measured in cerebrospinal fluid. Both patients had plasma levels of carbamazepine of 3.2 pg/ml and the corresponding concentrations in CSF were 0.70 and 0.71 pg/ml, respectively. The ratio between the concentration in CSF and in plasma (0.22) was in agreement with that obtained by Johannessen and Strandjord (1973). The corresponding concentrations of epoxide in plasma were O.61 and 1.O8 pg/ml, and in CSF 0.30 and 0.43 pg/ml, respectively. The higher CSF/plasma ratio (.45) of the epoxide indicates that the unbound fraction of this metabolite was of the order of 45 - 50%, in agreement with preliminary in vitro results obtained in the authors' laboratory. The unbound (free) fraction of a drug is considered to be the biologically active species. Assuming that the epoxide is as effective in man as in rat, it is quite
likely that the epoxide would contribute to a greater extent to the pharmacological action of carbamazepine than would be anticipated from its rather lower concentration in plasma than of carbamazepine. In thirteen patients seizure control was assessed (Table 2). The frequency of grand mal seizures did not change. In seven patients the number of partial seizures was reduced by 10 to 70% during treatment with carbamazepine, and in five the number of partial seizures increased (range 10 to 100 percent). One patient had the same number of partial seizures during the two periods. The mean plasma concentration of carbamazepine did not differ between the two groups (4.5 and 4.7 ~g/ml, respectively), nor did the total of carbamazepine and its epoxide (6.1 and 5.6 pg/ml). Thus, in this group of ambulant epileptic patients treated with optimal doses of diphenylhydantoin the addition of carbamazepine in doses giving plasma levels of about 5 pg/ml did not reduce the frequency of partial or generalized epileptic seizures. This m a y have been due to too low plasma levels of carbamazepine. However, increasing the dose of carbamazepine in 5 patients (H.J., H.L., K.K., G.L., and T.R.) did not improve seizure control despite a rise of plasma level to between 7 and 8 pg/ml, although it evoked side effects in 3 patients (fatigue, vertigo, nausea). The inter-individual variability in the ratio between plasma concentrations of carbamazepine and its epoxide makes it desirable to monitor both of them in future studies aimed at correlation of the plasma level and clinical effect of the drug. Some individuals have now been found with epoxide levels approaching those of the parent drug, possibly as a result of induction of liver m i c r o s o m a l enzymes (of Eichelbaum et al., 1975). It would be of considerable interest to evaluate the clinical effects of carbamazepine in such individuals, because it might permit indirect assessment of the clinical effect of the metabolite. The study was supported by a grant from the Swedish Medical Research Council (3902-O3B). A fellowship from the Paul MartiniStiftung, Frankfurt/Main, West Germany (to M. E.) is gratefully appreciated.
Acknowledgements.
REFERENCES Bird, C.A.K., Griffin, B.P., Miklascewska, J. M., Galbraith, A.W.: Tegretol (carbamazepine): A controlled trial of a new anticonvulsant. Brit. J. Psychiat. 112, 737-742 (1966)
421
Blom, S.: Tic doloreux treated with a new anticonvulsant. Arch. Neurol. (Chic.) 9, 285 (1963) Bonduelle, M.: My study of Tegretol. In: Tegretol in epilepsy, Report of an International Clinical Symposium, London 1972, (ed. A.S. Wink), pp 80-88. Manchester: C. Nicholls and Co. Ltd 1972 Buchthal, F., Svensmark, O., Schiller, P.J.: Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin. Arch. Neurol. (Chic.) 2, 62463O (1960) Cereghino, J.J., van Meter, J.C., Brock, J.T.: Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology 23, 357-366 (1973) Cereghino, J.J., Brock, J.T., van Meter, J.C., Penry, J.K., Smith, L.D., White, B.G.: Carbamazepine for epilepsy. A controlled prospective evaluation. Neurology 24, 401410 (1974) Christiansen, J.: Assay of drugs and their metabolites in capillary blood. Scand. J. clin. Lab. Invest. Suppl. I18, 67 (1971) Eichelbaum, M., Bertilsson, L.: Determination of carbamazepine and its epoxide metabolite in plasma by high-speed liquid chromatography. J. Chromatogr. 103, 135-140 (1975) Eichelbaum, M., Ekbom, K., Ringberger, V.A., Bertilsson, L., Rane, A.: Plasma kinetics of carbamazepine and its epoxide metabolite in man during single and multiple dosing. Europ. J. clin. Pharmacol. 8, 337-341 (1975) Frey, H., Yrj~n~, T.: Carba/nazepine titers in epileptic patients. Scand. J. clin. Lab. Invest. Suppl. 113, 90 (1970) Frigerio, A., Fanelli, R., Biandrate, P., Passerini, G., Morselli, P.L., Garratini, S.: Mass spectrometric characterization of carbamazepine-lO,11-epoxide, a carbamazepine metabolite isolated from human urine. J. pharm. Sci. 61, 1144-1147 (1972) Johannesen, S., Strandjord, R.: Koncentrationen av karbamazepin i serum och cerebrospinal-
vatska hos 9 patienter med epilepsi. In: Plasmakoncentrationsbest~mningar av antiepileptika (ed. L. Lund), pp. 25-26, LidingS: Geigy L~kemedel 1971 Johanneson, S., Strandjord, R.E. Concentration of carbamazepine in serum and in cerebrospihal fluid in patients with epilepsy. Epilepsia 14, 373-379 (1973) Kutt, H., Haynes, J., Mc Dowell, F.: Some causes of ineffectiveness of diphenylhydantoin. Arch. Neurol. 14, 489-492 (1966) Lund, L.: Anticonvu!sant effect of diphenylhydantoin in relative to plasma levels. Arch Neurol. (Chic.) 31, 289-294 (1974) Meinardi, H.: Carbamazepine. In: Antiepileptic drugs, (eds. D.M. Woodbury, J.K. Penry, R. P. Schmidt), pp. 487-496. New York: Raven Press 1972 M~ller, J.: Serumkoncentrationsbest~mningar av karbamazepin inom barnneurologien. In: Plasmakoncentrationsbest~mningar av antiepileptika (ed. L. Lund) pp. 72-78. Liding6: Geigy L~kemedel 1971 Morselli, P.L., Gerna, M., Garratini, S.: Carbamazepine plasma and tissue levels in the rat. Biochem. Pharmacol. 20, 2043-2047 (1971) Morselli, P.L., Biandrate, P., Frigerio, A., Gerna, M., Tognoni, G.: In: Methods of analysis of antiepileptic drugs, (eds. J.W.A. Meijer, H. Meinardi, C. Gardner Thorpe, E. van der Kleijn), p. 169. Amsterdam: Excerpta Medica 1973 Palm~r, L., Bertilsson, L., Collste, P., Rawlins, M.: Quantitative determination of carbamazepine in plasma by mass fragmentography. Clin. Pharmacol. Ther. 14, 827832 (1973)
Dr. L. Lund Department of Neurology Huddinge Hospital S-141 86 Huddinge Sweden
Plasma Levels of Carbamazepine and Carbamazepine-10,11-epoxide during Treatment of Epilepsy M. Eichelbaum*, L. Bertilsson**, L. Lund, L. Palrn6r and F. Sj6qvist Departments of Clinical Pharmacology, Huddinge Hospital, Neurology, Karolinska Hospital and Toxicology, Karolinska Institute, Stockholm, Sweden
Received: May 5, 1975, accepted: September 10, 1975
Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 ± 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 ± 2.5 ~g/ml and 1.10 ± 0.42 ug/ml, respectively. A significant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p O . 0 5 )
Table
2. N u m b e r
in c o m b i n a t i o n
of s e i z u r e s with
and plasma
I
I
I
I
l
I
I
I
2
3
4
5
6
7
8
9 10 11 12 1 3 1 4 15
a
I
I
!
I
I
~ g carbamazepine/mtplasma
Fig. 2. R e l a t i o n s h i p b e t w e e n p l a s m a c o n c e n t r a t i o n of c a r b a m a z e p i n e a n d its e p o x i d e m e t a b o l i t e in e p i l e p t i c p a t i e n t s (r = 0.64; p < O . O 0 1 )
concentrations
of d r u g s
during
treatment
with
DPH
alone
partial seizures
6 months
mean DPH plasma concentration
Treatment with DPH and carbamazepine Total number of grand mal partial seizures seizures
ug/ml
during 6 months
mean DPH plasma concentration pg/ml
range of the p l a s m a concentrations of carbamazepine
~g/ml
change in partial seizure between the two periods iin %)
30
16.O
-
27
16.4
4.8-7.9
-10
L.B.
0
8
13.0
I
i0
14.2
3.9-5.2
+25
C.E.
-
6
15.3
2
16.8
4.9
-67
H.J.
-
42
15.O
M.K.
-
22
]4.2
H.L.
2
64
B.L.
-
42
K.K.
4
120
15.O
G.L.
-
35
E.O.
2
12
E.R.
-
5
15.O
C.R.
1
8
15.2
P.W.
3
140
20.2
3
R.B.
and
carbamazepine
Treatment with DPH during Total number of grand mal seizures
I
1
47
17.2
3.5-6.9
+I0
-
16
16.O
3.2-4.5
-30
18.O
i
59
17.2
4.3-6. i
-i0
16.O
-
30
16.8
4.9
-30
5
132
15.2
5.0-8.2
+i0
12.0
-
52
13.4
2.9-6.5
+50
15.2
2
11
16.0
2.9-3.0
0
-
2
14.2
5.1-5.5
-60
0
17
15.9
I .4-3.9
+iOO
125
19.8
4.5-6.7
-IO
420
mass fragmentography according to Palmer et al. (1973). The correlation between the two methods of r = 0.99 has previously been reported (Eichelbaum and Bertilsson, 1974). Plasma levels quoted in this report were obtained by liquid chromatography.
RESULTS AND DISCUSSION The prescribed doses of carbamazepine and DPH and the concentrations of DPH, carbamazepine, carbamazepine-10,11epoxide and the ratio between the latter two for each of the 25 patients studied are shown in Table I. The mean concentrations of carbamazepine and its epoxide were 5.4 ± 2.5 pg/ml and 1.10 ± 0.42 pg/ml, respectively (n = 25). The m e a n daily dose of carbamazepine was 12.5 ± 3.3 mg/kg body weight (n = 25). In Fig. I the prescribed daily dose of carbamazepine has been plotted against the plasma level of carbamazepine. Regression analysis showed no significant correlation (r = 0.19) between them, implying that the plasma concentration achieved cannot readily be predicted from the prescribed dose. The relationship between the concentration of carbamazepine and its epoxide in plasma (r = 0.64) is shown in Fig. 2. This correlation indicates that change in the plasma level of carbamazepine will usually result in a proportional change in the concentration of the epoxide. However, there was interindividual variation in the ratio between parent compound and metabolite, the latter reaching levels between 15 and 55% of the former. In two patients the concentration of carbamazepine and its epoxide were measured in cerebrospinal fluid. Both patients had plasma levels of carbamazepine of 3.2 pg/ml and the corresponding concentrations in CSF were 0.70 and 0.71 pg/ml, respectively. The ratio between the concentration in CSF and in plasma (0.22) was in agreement with that obtained by Johannessen and Strandjord (1973). The corresponding concentrations of epoxide in plasma were O.61 and 1.O8 pg/ml, and in CSF 0.30 and 0.43 pg/ml, respectively. The higher CSF/plasma ratio (.45) of the epoxide indicates that the unbound fraction of this metabolite was of the order of 45 - 50%, in agreement with preliminary in vitro results obtained in the authors' laboratory. The unbound (free) fraction of a drug is considered to be the biologically active species. Assuming that the epoxide is as effective in man as in rat, it is quite
likely that the epoxide would contribute to a greater extent to the pharmacological action of carbamazepine than would be anticipated from its rather lower concentration in plasma than of carbamazepine. In thirteen patients seizure control was assessed (Table 2). The frequency of grand mal seizures did not change. In seven patients the number of partial seizures was reduced by 10 to 70% during treatment with carbamazepine, and in five the number of partial seizures increased (range 10 to 100 percent). One patient had the same number of partial seizures during the two periods. The mean plasma concentration of carbamazepine did not differ between the two groups (4.5 and 4.7 ~g/ml, respectively), nor did the total of carbamazepine and its epoxide (6.1 and 5.6 pg/ml). Thus, in this group of ambulant epileptic patients treated with optimal doses of diphenylhydantoin the addition of carbamazepine in doses giving plasma levels of about 5 pg/ml did not reduce the frequency of partial or generalized epileptic seizures. This m a y have been due to too low plasma levels of carbamazepine. However, increasing the dose of carbamazepine in 5 patients (H.J., H.L., K.K., G.L., and T.R.) did not improve seizure control despite a rise of plasma level to between 7 and 8 pg/ml, although it evoked side effects in 3 patients (fatigue, vertigo, nausea). The inter-individual variability in the ratio between plasma concentrations of carbamazepine and its epoxide makes it desirable to monitor both of them in future studies aimed at correlation of the plasma level and clinical effect of the drug. Some individuals have now been found with epoxide levels approaching those of the parent drug, possibly as a result of induction of liver m i c r o s o m a l enzymes (of Eichelbaum et al., 1975). It would be of considerable interest to evaluate the clinical effects of carbamazepine in such individuals, because it might permit indirect assessment of the clinical effect of the metabolite. The study was supported by a grant from the Swedish Medical Research Council (3902-O3B). A fellowship from the Paul MartiniStiftung, Frankfurt/Main, West Germany (to M. E.) is gratefully appreciated.
Acknowledgements.
REFERENCES Bird, C.A.K., Griffin, B.P., Miklascewska, J. M., Galbraith, A.W.: Tegretol (carbamazepine): A controlled trial of a new anticonvulsant. Brit. J. Psychiat. 112, 737-742 (1966)
421
Blom, S.: Tic doloreux treated with a new anticonvulsant. Arch. Neurol. (Chic.) 9, 285 (1963) Bonduelle, M.: My study of Tegretol. In: Tegretol in epilepsy, Report of an International Clinical Symposium, London 1972, (ed. A.S. Wink), pp 80-88. Manchester: C. Nicholls and Co. Ltd 1972 Buchthal, F., Svensmark, O., Schiller, P.J.: Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin. Arch. Neurol. (Chic.) 2, 62463O (1960) Cereghino, J.J., van Meter, J.C., Brock, J.T.: Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology 23, 357-366 (1973) Cereghino, J.J., Brock, J.T., van Meter, J.C., Penry, J.K., Smith, L.D., White, B.G.: Carbamazepine for epilepsy. A controlled prospective evaluation. Neurology 24, 401410 (1974) Christiansen, J.: Assay of drugs and their metabolites in capillary blood. Scand. J. clin. Lab. Invest. Suppl. I18, 67 (1971) Eichelbaum, M., Bertilsson, L.: Determination of carbamazepine and its epoxide metabolite in plasma by high-speed liquid chromatography. J. Chromatogr. 103, 135-140 (1975) Eichelbaum, M., Ekbom, K., Ringberger, V.A., Bertilsson, L., Rane, A.: Plasma kinetics of carbamazepine and its epoxide metabolite in man during single and multiple dosing. Europ. J. clin. Pharmacol. 8, 337-341 (1975) Frey, H., Yrj~n~, T.: Carba/nazepine titers in epileptic patients. Scand. J. clin. Lab. Invest. Suppl. 113, 90 (1970) Frigerio, A., Fanelli, R., Biandrate, P., Passerini, G., Morselli, P.L., Garratini, S.: Mass spectrometric characterization of carbamazepine-lO,11-epoxide, a carbamazepine metabolite isolated from human urine. J. pharm. Sci. 61, 1144-1147 (1972) Johannesen, S., Strandjord, R.: Koncentrationen av karbamazepin i serum och cerebrospinal-
vatska hos 9 patienter med epilepsi. In: Plasmakoncentrationsbest~mningar av antiepileptika (ed. L. Lund), pp. 25-26, LidingS: Geigy L~kemedel 1971 Johanneson, S., Strandjord, R.E. Concentration of carbamazepine in serum and in cerebrospihal fluid in patients with epilepsy. Epilepsia 14, 373-379 (1973) Kutt, H., Haynes, J., Mc Dowell, F.: Some causes of ineffectiveness of diphenylhydantoin. Arch. Neurol. 14, 489-492 (1966) Lund, L.: Anticonvu!sant effect of diphenylhydantoin in relative to plasma levels. Arch Neurol. (Chic.) 31, 289-294 (1974) Meinardi, H.: Carbamazepine. In: Antiepileptic drugs, (eds. D.M. Woodbury, J.K. Penry, R. P. Schmidt), pp. 487-496. New York: Raven Press 1972 M~ller, J.: Serumkoncentrationsbest~mningar av karbamazepin inom barnneurologien. In: Plasmakoncentrationsbest~mningar av antiepileptika (ed. L. Lund) pp. 72-78. Liding6: Geigy L~kemedel 1971 Morselli, P.L., Gerna, M., Garratini, S.: Carbamazepine plasma and tissue levels in the rat. Biochem. Pharmacol. 20, 2043-2047 (1971) Morselli, P.L., Biandrate, P., Frigerio, A., Gerna, M., Tognoni, G.: In: Methods of analysis of antiepileptic drugs, (eds. J.W.A. Meijer, H. Meinardi, C. Gardner Thorpe, E. van der Kleijn), p. 169. Amsterdam: Excerpta Medica 1973 Palm~r, L., Bertilsson, L., Collste, P., Rawlins, M.: Quantitative determination of carbamazepine in plasma by mass fragmentography. Clin. Pharmacol. Ther. 14, 827832 (1973)
Dr. L. Lund Department of Neurology Huddinge Hospital S-141 86 Huddinge Sweden
