A Preliminary Study of Serum Carbamazepine Levels in Healthy Subjects and in Patients with Epilepsy

Strandjord, R. E.; Johannessen, Svein I.

doi:10.1007/978-3-642-85921-2_17

Cited by 17 publications

(11 citation statements)

References 12 publications

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“…In fact, no significant correlation (n = 93; r = 0.19) was observed between the prescribed dose and the plasma concentration of carbamazepine in 25 epileptic patients treated for at least 6 months with the drug (Eichelbaum et at., I 976a.,b). Such a poor correlation has also been shown by other investigators (Meinardi, 1972;Christiansen and Dam, 1973;Hooper et aI., 1974;Johannessen and Strandjord, 1975;Schneider, 1975b;Morselli et ai., 1976). Meinardi (1972) showed in 2 patients that doubling the dose of carbamazepine doubled the plasma level of the drug.…”

Section: Effect 0/ Dose Sizesupporting

confidence: 54%

“…2.1.1 Absorption Slow absorption has been found after the oral administration of single doses of Tegretol tablets (Gauchel et a!., 1973;Palmeret a!., 1973;Levy et ai., 1975b;Morselli et aI., 1975;Strandjord and Johannessen, 1975;Rawlins et aI., 1975;Eichelbaum et a!., 1975). Peak plasma concentrations have been obtained as late as 24 hours after the dose (Faigle et a!., 1976;Gerardin and Hirtz, 1976).…”

Section: Fundamental Properties In Volunteers and Patientsmentioning

confidence: 95%

“…or phenobarbitone (Christiansen and Dam, 1973;Johannessen and Strandjord, 1975;Schneider, I 975b). Treatment with all 3 drugs produced the lowest plasma levels of carbamazepine.…”

Section: Combination With Other Antiepileptic Drugsmentioning

confidence: 98%

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Clinical Pharmacokinetics of Carbamazepine

Bertilsson

1978

Clinical Pharmacokinetics

212

108

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Carbamazepine seems to as effect as phenytoin in the treatment of grand mal and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia. After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10-20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics. Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10,11-epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine doses has been identified as metabolites in the urine. The quantitatively most important metabolites is the trans-10,11-dihydro-10,11-diol. The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults. A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects. Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10microgram/ml (20 to 40mumol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.

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Section: Effect 0/ Dose Sizesupporting

confidence: 54%

Section: Fundamental Properties In Volunteers and Patientsmentioning

confidence: 95%

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Clinical Pharmacokinetics of Carbamazepine

Bertilsson

1978

Clinical Pharmacokinetics

212

108

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“…Of significance for the clinical use of carb amaze pine , is the change in serum half-life after a few weeks of treatment. A reduction of the half-life from about 35 to about 20 hours is no t rare (Levy et aI., 1975b;Eichelbaum et al, 1975;Strandjord and Johannessen, 1975). This is due to self-induction and means that single dose studies prior to treatment cannot be expected to have predictive value for the steady state level.…”

Section: Elimination Kineticsmentioning

confidence: 97%

Clinical Pharmacokinetics of Anticonvulsants

Hvidberg

Dam

1976

Clinical Pharmacokinetics

141

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Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half-life of phenobarbitone is only half of that in adults. An optimum therapeutic plasma range has been established and monitoring is recommended. Primidone may have an anticonvulsant activity in itself, but its main metabolite is phenobarbitone. The relatively rapid elimination of primidone is offset by the long half-life of phenobarbitone. An optimum therapeutic range has been suggested, but plasma level monitoring must include determination of phenobarbitone. Ethosuximide. The clinical pharmacokinetics of this important petit mal anticonvulsant is not well known. It has a relatively long half-life (in adults 2 to 3 days; in children shorter). An optimum therapeutic range has been suggested, and routine monitoring of plasma levels may be recommended. Diazepam exerts a repid anticonvulsant activity when the plasma concentration exceeds approximately 500ng/ml after intravenous injection. The kinetic pattern is complex in man. Clonazepam. The clinical pharmacokinetics are still not fully investigated but a therapeutic range has been suggested...

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“…Strandjord and Johannessen (31) suggested that the observed variations may be due to differences in the specificity of the different methods employed or individual differences in absorption or elimination of the compound.…”

Section: Introductionmentioning

confidence: 99%

Circadian effect on carbamazepine kinetics in rat

Bruguerolle

Valli

Bouyard

et al. 1981

European Journal of Drug Metabolism and Pharmacokinetics

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The purpose of the present study was to investigate whether the time of day (24 h) at which carbamazepine is administered influences its pharmacokinetics in the rat. The pharmacokinetics of a single, 100 mg . kg-1 bodyweight per os, dose of carbamazepine were studied at four different fixed time points of a 24-hour period (i.e. 10.00, 16.00, 22.00 or 04.00 h) in Wistar AF-SPF adult male rats maintained under controlled environmental conditions (LD: 18.00 - 06.00h) during October 1978. The total plasma levels and the unbound fraction were measured according to an immunoenzymatic method (EMIT). The effects of fasting were also investigated. The data shows circadian variations of pharmacokinetic parameters: the maximum peak concentration and the maximum time to reach this peak was observed when the drug was given respectively at 16.00h and at 10.00h. The elimination half-life varied from 15.15 hours at 16.00h to 10.48 hours at 22.00h. The observed variations may be related to: daily fluctuations of absorption or binding of the drug; diurnal variations of the hepatic drug metabolizing enzymes responsible for the inactivation; and/or diurnal variations in excretion rate of the drug.

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A Preliminary Study of Serum Carbamazepine Levels in Healthy Subjects and in Patients with Epilepsy

Cited by 17 publications

References 12 publications

Clinical Pharmacokinetics of Carbamazepine

Clinical Pharmacokinetics of Carbamazepine

Clinical Pharmacokinetics of Anticonvulsants

Circadian effect on carbamazepine kinetics in rat

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