Citation

Klys M, Bystrowska B, Bujak-Gizycka B. J. Anal. Toxicol. 2003; 27(4): 243-248.

Copyright

(Copyright © 2003, Preston Publications)

DOI

10.1093/jat/27.4.243

PMID

unavailable

Abstract

The study focuses on a series of 16 fatal cases in which carbamazepine and its two major metabolites (10,11-epoxide and 10,11-dihydroxycarbamazepine) were detected in body fluids and tissues collected at autopsy. The drug may be implicated in a number of deaths; however, most of these are multiple-drug intoxications with a particular contribution of ethanol. The investigations concerning toxicological findings are a source of toxicological postmortem data and show the differences in metabolism rate as depending on the concentration level of carbamazepine and xenobiotics found in the autopsy specimen during the postmortem investigation of a body.; FreeText:Postmortem autopsy specimens, samples of femoral blood, liver, and kidney were collected at autopsy. Parallel with the materials taken from the authentic subjects, standards of Tegretol, CBZ-E, and CBZ-DHD and "blank" samples of autopsy blood and liver taken from nonpoisoned subjects spiked with these drugs were investigated. The latter materials were used to facilitate identification, quantitation, and validation by means of liquid chromatography-mass spectrometry (LC-MS). Calibration curves were constructed after the analysis of drug-free blood and liver samples (blank samples) containing known amounts of Tegretol, CBZ-E, and CBZ-DHD. The parent drug to metabolites (P/M) concentration ratio was calculated.; Patients:16 patients, 10 males and 6 females, age range 7-70 years.; TypeofStudy:The levels of Tegretol and its two major metabolites (carbamazepine 10,11-epoxide [CBZ-E] and carbamazepine 10,11 dihydroxycarbamazepine [CBZ-DHD]) in blood and tissues collected at autopsy in a series of 16 fatal cases was reported.; DosageDuration:Dosage and duration not stated.; Results:6 subjects were probable suicides, 5 were accidents, 2 natural deaths, 1 homicide, and in 2 cases the manner of death could not be determined. The death of 4 cases was attributed to Tegretol alone. The blood level ranged from 16 mcg/g in case 2 to almost 100 mcg/g in case 3. In the liver, the upper limit of Tegretol found was almost twice as high (case 3). Case 3 has a very high concentration level of metabolites in the blood, whereas in the liver CBZ-E reached an inexplicably low value as opposed to CBZ-DHD, which was twice as high as CBZ-DHD in relation to Tegretol. Cases 5-7 showed therapeutic concentrations of Tegretol plus low levels of its metabolites, ruling that death in these cases were because of other causes. 9 cases (cases 8-16) presented here with lower concentration levels of Tegretol, in the range from therapeutic to fatal, also had certain concentrations of other xenobiotics including ethanol, benzodiazepines, and morphine, which emphasizes the importance of taking into consideration potential interactions with other drugs or preexisting disease (e.g., epilepsy). As to the possibility of interactions between the mentioned xenobiotics, Tegretol was considered to be a factor contributing to toxicity in these deaths. In these 9 cases, 4 (cases 8-11) were considered combined Tegretol/ethanol intoxications. The concentration of ethanol in blood was low, whereas in urine it was significantly higher indicating death in the late phase of elimination. The remaining 5 cases (cases 12-16) were mixed-drug intoxications, in which Tegretol and its metabolites were found together with other drugs. The lowest P/M values can be noted in cases involving only Tegretol, whereas the highest values were found in cases of combined Tegretol/ethanol intoxications (cases 8-11). An intermediate position is taken by cases involving Tegretol and other drugs such as estazolam, phenobarbital, and diazepam. These relationships are especially clear in the blood and kidney. Because the concentrations of metabolites in the liver in mixed cases were low (including negative values), or even not measurable in mixed intoxications of Tegretol and other drugs, the P/M ratios for this tissue show high values.; AdverseEffects:13 fatal drug intoxications.; AuthorsConclusions:Because the literature on postmortem concentration levels of xenobiotics involved in fatal intoxications is mainly available in the form of case reports, we hope that this study will contribute to the database extending the field of forensic toxicology.

Language: en