Published: Journal of Analytical Toxicology, Volume 20, Number 4, July/August 1996, pp. 273.

Zopiclone Poisoning
D. Pounder and J. Davies

To the Editor:
Van Bocxlaer et al. (1) have described a case of poisoning by zopiclone, which is a cyclopyrrolone, third-generation hypnotic. They found drug concentrations of 0.15 mg/g in stomach contents, 5.10 µg/g in liver, and 1.18 µg/mL in blood (sampling site unspecified). In a similar fatality case (2), we found concentrations ranging from 0.9 to 2.0 µg/mL in ten distinct blood sampling sites. After allowing the body to lie undisturbed for 40 h, we drew 15 additional blood samples, which disclosed concentrations of 0.9 to 1.8 µg/mL. From this we concluded that postmortem blood levels of zopiclone are relatively stable and little influenced by postmortem drug redistribution (3), which is consistent with the known low volume of distribution, approximately 1.5 L/kg (4). Both bile and urine were available for analysis and contained zopiclone at concentrations of 14.1 and 10.5 µg/mL, respectively. In solid organs, the highest drug concentrations were found in the spleen (5.8 µg/g), but this may reflect postmortem diffusion from gastric contents (55.1 µg/mL). Liver concentrations measured up to 4.9 µg/g, but they were site-variable and ranged between 0.5 and 4.9 µg/g in eight samples. The highest concentrations were in the left lobe, and the lowest concentrations were in the right lobe. This 10-fold range in concentration of zopiclone in the liver most likely reflects postmortem diffusion from the stomach and emphasizes the desirability of obtaining a liver sample from deep within the right lobe (5). Consequently, the liver concentration of zopiclone reported by Van Bocxlaer and co-workers should be viewed with caution.

After quantitating zopiclone in 21 solid organ samples, including fat and skeletal muscle, we calculated body load of the drug by adding the drug load of each major tissue or organ, which was calculated from the drug concentration and organ weight. By this method, the body load of zopiclone was estimated as 111 mg. For comparative purposes, body drug load, which was calculated by volume of distribution (Vd) (Vd = 1.5 L/kg; body weight = 64 kg; femoral venous blood concentration = 1.2 µg/mL), was 91 mg. Thus, it appears that calculation of the ingested dose of zopiclone by the Vd method is likely to be reasonably accurate, given that zopiclone does not show significant postmortem redistribution. This may prove to be of considerable assistance in the interpretation of zopiclone blood levels in fatalities.

Derrick Pounder and Justine Davies
Department of Forensic Medicine
University of Dundee
The Royal Infirmary
Dundee DD1 9ND
Scotland

References

1. J. Van Bocxlaer, E. Meyer, K. Clauwaert, W. Lambert, M. Piette, and A. De Leenheer. Analysis of Zopiclone (Imovane®) in postmortem specimens by GC–MS and HPLC with diode-array detection. J. Anal. Toxicol. 20: 52–54 (1996).
2. D.J. Pounder and J.I. Davies. Zopiclone poisoning: tissue distribution and potential for postmortem diffusion. Forensic Sci. Int. 65: 177–83 (1994).
3. D.J. Pounder. The nightmare of postmortem drug changes. Legal Medicine. C.H. Wecht, Ed. Buttersworth, Salem, 1993,
   pp 163–91.
4. K.L. Goa and R.C. Heel. Zopiclone—a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as a hypnotic. Drugs 32: 48–65 (1986).
5. D.J. Pounder, E. Adams, C. Fuke, and A. Langford. Site to site variability of postmortem drug concentrations in liver and lung.
   J. Forensic Sci., in press.

The authors reply:
We fully agree with Pounder and Davies’ comments on the postmortem diffusion of zopiclone from the stomach. This statement also holds true for several other drugs. Consequently, in all autopsies carried out by our group, a specimen of the right liver lobe is always taken in a standardized procedure for further toxicological analysis.

The rather high concentration of zopiclone we found in that part of the liver (5.10 µg/g) could be a result of a longer death agony of the deceased, which would allow time for the liver zopiclone concentration to increase (1).

J. Van Bocxlaer1, E. Meyer¹, K. Clauwaert¹, W. Lambert¹, M. Piette², and A. De Leenheer^1
1Laboratorium voor Toxicologie and ² Universiteit Gent
B-9000 Gent
Belgium

Reference

1. P.J. Boniface and S.G. Russell. Two cases of fatal zopiclone overdose. J. Anal. Toxicol. 20: 131–33 (1996).

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