Carbamazepine Poisoning: Elimination Kinetics and Quantitative Relationship with Carbamazepine 10,11-Epoxide

Abstract

Carbamazepine (amizepine) is a widely used psychotropic agent. A much easier accessibility of this drug, observed during the recent years, may account for an increasing number of acute intoxications with carbamazepine. The aim of this study was to determine the elimination kinetics of carbamazepine and its metabolite carbamazepine 10,11-epoxide, and to identify the quantitative relationship between concentrations of these compounds, in serum. The subjects were 41 patients with acute carbamazepine intoxication. Serum carbamazepine and carbamazepine 10,11-epoxide concentrations were determined every 6 hours during thefirst 24 hours of hospitalization, and then every 12 hours. At the same time, urinalyses were performed for each patient to confirm or exclude homogeneity of poisoning. Depending on the type of intoxication (homogenous or combined), three groups of patients, and on the method of treatment (symptomatic, charcoal administration), two groups of patients were distinguished. The statistical analysis of the results revealed that among the investigated parameters (time-integrated concentrations of carbamazepine and carbamazepine 10,11-epoxide in serum, the presence of drugs, and/or ethanol, charcoal treatment) only carbamazepine concentrations had statistically significant effect on the duration of coma regarded as a critical effect. The kinetics of carbamazepine elimination was determined on the basis of the mean carbamazepine concentrations at the same timing of sampling for each patient in all the three groups; the mean carbamazepine elimination in serum followed zero-order kinetics. In individual groups, the decrease in serum carbamazepine concentrations ranged from 0.5 to 0.8 mg L(-1) hour(-1). Contrary to the suggestions found in the literature, carbamazepine 10,11-epoxide determination does not seem to enhance the possibility of anticipating the course of intoxication or the time of recovery.

The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation

“…Retrospective and observational studies suggest that the reference ranges for CBZ and CBZE are 4-12 mg/L and 0.8-3.2 mg/L, respectively [5,17] . The reference range has been a controversial concept, partly because it was initially defined on the basis of limited data for individual AEDs, which may not describe adequately the concentrationresponse relationship in patients with epilepsy [7] .…”

“…CBZE is thought to be partially responsible for the toxicity of CBZ treatment [3] . The poor rela-tionship between dose and blood levels and the high intraand inter-individual variability of those levels were observed in CBZ therapy [1,4,5] . In addition, CBZ treatment can be further complicated by concomitant use of other AEDs with induction and inhibition properties, which may have an impact on the pharmacokinetic profiles of both CBZ and CBZE [6] .…”

Pharmacokinetics of carbamazepine polymorphs and dihydrate in rats, related to dogs and humans

“…Several authors have reported that the plasma levels of CBZ-10, 11-epoxide (CBZ-E), which is the main metabolite of CBZ, were very low and could be measured accurately only up to 72 h after a single dose of the parent drug (Eichelbaum et al, 1975;Winnicka et al, 2002). The plasma concentration of CBZ-E was too low to be measured following administration of the single dose used in the present study.…”

“…Data for humans were adapted from those reported in the literature (Cotter et al, 1977;Kahela et al, 1983;Gérardin et al, 1990;Winnicka et al, 2002;Elqidra et al, 2004), while the data for dogs were obtained mainly from Kobayashi et al (2000) and Kou et al (2011). The main PK parameters of CBZ in species are compared in Table II.…”

Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose

“…23 Elimination of carbamazepine would also have been delayed without intervention; in the setting of elevated serum concentrations, as seen in overdose, zero-order kinetics are observed (a fixed amount of drug is eliminated per unit of time). 24 To definitively demonstrate which modality (plasmapheresis or continuous venovenous hemodialysis) was most effective in eliminating carbamazepine from the patient would require measurement of carbamazepine concentration in the dialysate and pheresate. Our institution did not previously have laboratory protocols for this process; we have subsequently developed procedures for any future cases.…”