Europ.J.clin.Pharmacol. 8, 337-341 (1975) © by Springer-Verlag 1975
Plasma Kinetics of Carbamazepine and Its Epoxide Metabolite in Man after Single and Multiple Doses M. Eichelbaum, K. Ekbom, L. Bertilsson, V.A. Ringberger and A. Rane Department of Clinical Pharmacology, Karolinska Institutet, Huddinge Hospital, Huddinge, and Department of Neurology, SSdersjukhuset, Stockholm, Sweden Received: August I0, 1974, and in revised form: December ii, 1974
Summary. Carbamazepine (Tegretol®) was administered orally to four patients as a single dose, and one week later three times daily for 15-21 days. The plasma half-lives of the drug were shorter in all patients after multiple doses (20.9 ± 5.0 hours) than after the initial single dose (35.6 ± 15.3 hours). During multiple doses the plasma concentrations of the metabolite carbamazepine-lO.llepoxide followed those of the parent drug. The steady-state plasma concentrations expected during multiple doses were calculated from the pharmacokinetic parameters obtained in the single dose studies. The calculated levels were higher (17.2 ± 7.2 ~g/ml) than the observed maximal concentrations (8.4 ± 1.6 ~g/ml on day 4), which were obtained 3-4 days after starting the multiple doses. The levels tended to decrease further during the experimental period. The results suggest that carbamazepine induces its own metabolism in man.
Key words: Carbamazepine, carbamamazepine-lO,ll-epoxide, pharmacokinetics, induction of metabolism, man.
Carbamazepine (Tegretol ®) is used in the treatment of convulsive disorders and trigeminal neuralgia. In a recent study (12), healthy volunteers were given single oral doses of carbamazepine and from the kinetic parameters obtained, the theoretical steady-state plasma concentrations during repetitive dosing were calculated. As the predicted concentrations were 3-4 times higher than the levels actually observed in patients treated chronically with the same or higher doses of carbamazepine (i, 2, 3, 8, 9), it was suggested that carbamazepine induces its own metabolism during prolonged treatment. Further support for this hypothesis stems from the observation that the plasma half-lives of carbamazepine in neonates, who had obtained the drug transplacentally from their epileptic mothers, were of the order of 10-27 hours (unpublished results), compared to 24-44 hours in healthy adult volunteers receiving single doses (12). The newborn babies may be considered to have had steadystate plasma concentrations of the drug before delivery. Thus, the rapid elimination of carbamazepine from plasma after birth may be due to induction of its metabolism during the gestational period.
Carbamazepine is partly metabolized to carbamazepine-lO,ll-epoxide, which has been identified in urine (6) and plasme (4) of man. In the rat the epoxide metabolite is as potent as the parent compound in preventing electroshock-induced seizures (IO). It is necessary, therefore, to measure the parent drug and its active metabolite, as both may contribute to the therapeutic effect of the drug. A recently reported (4) liquid chromatographic method for the simultaneous determination of the two compounds in plasma was used in this study to investigate the kinetics of carbamazepine and the epoxide (formed in vivo) after single and multiple doses.
Materials and Methods Patients, Drug Administration and Collection of Plasma Four male in-patients, aged 49-59 years, participated voluntarily in the study. They received carbamazepine therapy for headaches (case E.J.), oral dyskinesia (case R.A$ and cerebellar tremor
(cases E.R. and R.S.). The latter two patients had also previously had a Billroth II partial gastrectomy. Other drugs were not taken for two weeks preceding the study. Clinical and neurological examination was normal, except for the dyskinesia in case R.A., and signs of cerebellar dysfunction in cases E.R. and R.S. Laboratory tests were normal including haemoglobin concentration, sedimentation rate, white cell count, liver function tests, serum proteins, electrolytes, serum creatinine, endogenous creatinine and urinalysis. The regular intake of carbamazepine was supervised by trained nurses. Carbamazepine (Tegretol®; 200 mg commercial tablets) was administered as single oral dose at 8.00 a.m. after an overnight fast. No food or fluid were allowed until 3 hours after dosing. One week later multiple dose studies were undertaken. Carbamazepine 200 mg was given at 8.00 a.m. and 2.00 p.m. on the first day, and thereafter at 8.00 a.m., 2.00 p.m. and 8.00 p.m. for 20 days.
In case R.S. the multiple doses were discontinued after 15 days because of an intercurrent disease. The patients received no other drugs. Venous blood (IO ml) was collected into heparinized (Vacutainer) tubes at various times after dosing and, after separation by centrifugation, the plasma was stored at -20°C until analysed. During the multiple dose regime blood samples were taken before the morning dose, Analytical Technique The concentrations of carbamazepine and carbamazepine-lO,ll-epoxide in plasma were determined in duplicate by liquid chromatography (4). Calculation of Pharmacokinetic
Plasma elimination half-lives (T 1/2) were calculated by least squares linear regression analysis of log plasma concentration versus time. The
0.1. 0,05. 0
• ~=~'"--: ...... ;'i'_.' ..................
Fig. i. Plasma concentrations (pg/ml; ordinate) of carbamazepine ('-') and carbamazepine-lO,ll-epoxide (~-~) determined at various times (abscissa) in four patients (R.A., E.J., E.R., and R.S.) after single and multiple doses. The patients first received a single oral dose of 200 mg of carbamazepine (broken lines in the right hand graphs). After one week, they received 200 mg of carbamazepine t.d. s. for 15-21 days (left hand graphs). Unbroken lines in the right hand curves show the plasma concentrations of the parent drug and the epoxide metabolite after the last dose in the multiple dose regime. The steady-state plasma concentrations of carbamazepine during multiple doses shown in the figure ( .... ) were predicted from pharmacokinetic parameters obtained in the single dose experiments.
339 area under the total plasma concentration-time curve (AUC) in the single dose experiments was estimated by use of the trapezoidal rule and integration of the infinite area. Plasma clearance (Vp) and volume of distribution (Vdarea) of the drug were calculated according to the equations of Wagner (15). In these calculations the bioavailability of the drug was assumed to be 100%; this assumption is supported by observations by the manufacturer (Keberle, personal communication). The steady-state plasma concentration (Css) of carbamazepine, 200 mg eight hourly, was predicted from the single dose experiments according to Wagner et al. (14).
= F • Dose Vdarea- KeI'T
where T is dosage interval in h~rs, F the fraction of the dose reaching the systemic circulation, Vdarea the apparent volume of distribution, and Kel is the first-order rate constant of elimination.
Results After the administration of a single 200 mg tablet of carbamazepine to the four patients, maximum plasma concentrations of carbamazepine (about 2 ~g/ml) were found within 24 hours (Fig. I, right hand curves). They were followed by monoexponential decline of the plasma levels with half-lives ranging from 18.5 to 54.7 hours (mean 35.6 ± S.D. 15.3)(Table I). As it is known that the absorption of carbamazepine from the commercial tablet (Tegretol®) is slow (7, ii, 12), the half-lives were calculated from the last data points (48 168 hours after drug administration). The r-values were close to unity (0.9990 ± 0.0007). The pharmacokinetic parameters calculated from these experiments are given in Table i. For comparison, results from a previous study (12) in eight volunteers given a single oral dose of carbamazepine in alcoholic solution (3 mg/kg body weight) have also been included. The plasma levels of carbamazepine-lO,ll-epoxide were very low and could be measured accurately only up to 72 hours after a single dose of the parent drug. It was not possible, therefore, to
Table i. Pharmacokinetic parameters in four patients after single and multiple doses of carbamazepine. The steady-state plasma concentrations were predicted from the single dose data for a dose of carbamazepine 200 mg eight hourly Carbamazepine after a single dose
Patient Age Weight T 1/2 AUC (y) ( k g ) sod (~gfml (hours) x hours)
8.35 8.47 16.7 21.58 ±0.96 25.0
Results from ref 1 Mean Z S.D. 35.9 (n=8) 28.3 X
T 1/2 sod T If2 ss AUC Vdarea
Vp Pre(ml/min) dicted Css (~g/ml)
T i12 Conc. ss (~g/ml) (hours) on day no 4 21
On day no 14, the last day of multiple dosage in patient R.S. Plasma elimination half-life after single oral dose Plasma elimination half-life after multiple dosing Area under the plasma concentration curve Apparent volume of distribution Plasma clearance Steady-state plasma concentration
T 1/2 Conc. ss (~g/ml) (hours) on day no. 4 21
340 estimate any pharmacokinetic parameters of the metabolite. The levels of the epoxide were about 3-5% of those of the parent compound. In a subsequent experiment, 200 mg of carbamazepine was given to the same four patients thrice daily (twice during the first day) for 21 days (for only 15 days to patient R.S.). In all patients the plasma levels of carbamazepine and its metabolite reached their peak after 3-4 days (Fig. I, left hand curves; Table I) and they seemed to decrease during prolonged treatment. E.J. and R.A. were the patients first investigated. When it was found that the highest plasma levels in them had occurred on day 4, more frequent plasma samples were taken from the next two patients (E.R. and R.S.) during the first week of multiple doses. From the results obtained in the single dose experiments, the theoretical steady-state plasma levels of carbamazepine that should be reached after eight hourly doses of 200 mg were calculated. The predicted levels of 20.1, 23.6 and 18.0 ~g/ml in three of the patients (Table I) were much higher than those actually found. Patient E.R. had the shortest half-life observed so far after a single dose (18.5 hours). In him the predicted and observed steady-state plasma levels were of the same order of magnitude. After stopping treatment, the decline of carbamazepine concentrations in plasma was log linear, with half-lives ranging from 16.4 to 26.6 hours (mean 20.9 ± S.D. 5.0) in the four patients. Thus, the plasma disappearance of carbamazepine was considerably more rapid after multiple doses than after a single dose in the same subject. The plasma concentration curves of carbamazepine -lO,ll-epoxide formed in vivo after multiple doses of carbamazepine followed almost exactly those of the parent drug (Fig. I). The concentrations of the epoxide metabolite were about 15% of the levels of carbamazepine in all patients during steady state conditions. The post-steady state plasma elimination half-lives of the epoxide (mean 16.7 ± S.D. 5.0 hours) and the parent drug (mean 20.9 ± S.D. 5.0 hours) were of the same order of magnitude (Table i).
Discussion The following points suggest that carbamazepine induces its own metabolism during repeated administration: (i). The plasma elimination half-life of the drug was shorter after multiple than after single doses.(±±). The observed steady-state plasma concentrations in three of the patients were 2-4 times lower than those calculated from the single dose experiments. The calculations of the steady state plasma levels were based on the assumption that the elimination of carbamazepine would follow an open one-compartment model, although, according to Riegelmann et al. (13), it is impossible to exclude an open two-compartment model as a more appropriate description of its pharmacokinetic behaviour, particularly as no data are available about its i.v. administration. However, the assumption that the pharmacokinetic behaviour
of carbamazepine is sufficiently described by an open one-compartment model is supported by the present results in patient E.R. In him only a small difference in half-lives was observed after single (18.5 hours) and multiple (16.4 hours) doses, which indicates that the extent of induction in this patient was negligible. Consequently, the predicted and observed steady-state plasma levels were almost identical. The lower steady-state levels could also be explained by unreliable drug intake and/or a decrease in the bioavailability of the drug during multiple dosing. The first possibility is unlikely, since drug intake was supervised by nurses. Changes in bioavailability cannot be excluded, but neither of these possibilities can explain the decreased half-lives after multiple doses, since the elimination of carbamazepine followed first order kinetics. The highest plasma concentration of carbamazepine during repeated administration was obtained after 3-4 days, and then the levels tended to decrease slowly. The results indicate that induction had already taken place during the first week of treatment. This assumption is further supported by in vitro experiments. Thus, the rate of epoxide formation was three times higher than in controls when carbamazepine was incubated with liver microsomes isolated from rats pretreated with carbamazepine for four days (unpublished results). As the plasma concentration of the epoxide metabolite followed that of carbamazepine during multiple doses, the enzymes responsible for the oxidation of the drug were not saturated. This is in agreement with results from in vitro incubations of carbamazepine with rat liver microsomes, when epoxide formation was linear up to a concentration of 2 x 10 -4 M carbamazepine in the incubation medium (unpublished results). The observed falls in the plasma levels of carbamazepine in the multiple dose experiments may be of clinical importance in the control of epileptic seizures and paroxysmal pains. It is well known, for instance, that many patients suffering from trigeminal neuralgia are improved initially by carbamazepine, but are more difficult to manage on prolonged treatment. Improvement may be found during the first three days and, according to the results shown in Fig. I, plasma levels should be relatively high at this period of time. Furthermore, there seems to be a positive correlation between the dose level and clinical response. Thus, in relapses during long-term treatment, a small increase in dosage, for instance from 600 to 800 mg per day, may suffice to restore adequate control of trigeminal pain. The effect of small dose increments on clinical response may also be observed in the treatment of the lightning pains of tabes dorsalis (5). Determination of plasma concentration and pharmacokinetic characteristics of carbamazepine may be important in patients who are therapeutic failures on long-term treatment. The relatively high initial plasma levels of carbamazepine, which were followed by a progres-
341 sive fall to an apparent steady state level, may be the kinetic correlate of the well known fact that initial side effects tend to vanish as treatment continues. This idea is strengthened by the observation that the plasma kinetics of the epoxide parallel that of the parent drug. The epoxide is probably pharmacologically active in man, provided that animal data can be extrapolated to him. Patients E.R. and R.S. both complained of slight drowsiness during the first four days of treatment, which may be a possible side-effect of carbamazepine therapy. A low initial dose and a step-wise increase of dosage may therefore be advisable.
This project was supported by grants from the Swedish Medical Research Council (B74-O4X-3902-O3B and 3902), Stiftelsen Margaretahemmet, the Association of the Swedish Pharmaceutical Industry, and Karolinska Institutet. A fellowship from the Paul Martini-Stiftung, Frankfurt/Main, West Germany (to M.E.) is gratefully appreciated.
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Dr. M. Eichelbaum Dept. of Medicine Univ. of Bonn D-5300 Bonn-Venusberg Germany