AUTHOR’S RESPONSE

We thank Dr. Šesták, Dr. Mžik and Prof. Dr. Hejna for their comments regarding our recent case report (1). We collected a blood sample from the femoral vein and subjected it to toxicological analysis. As you may be aware, Schulz’s article not only includes biological data, but also postmortem data, and we have used their study as a reference (2). Although “toxic concentration” is widely used in the literature (3,4), it may be important to consider using “laboratory alert level”, as you recommended.

In addition, thank you for suggesting several useful references (5,6), which showed that the median drug concentration is generally likely to reflect normal postmortem (PM) concentrations. Specifically, Launiainen and Ojanperä showed that the normal PM concentrations of levomepromazine and olanzapine were approximately 0.40 µg/ml and 0.20 µg/ml, respectively (5). Further, Söderberg et al. showed that the median PM concentration of olanzapine was 0.10 µg/ml and that the 90^th percentile was 0.20 µg/ml in a non-intoxication group (6,7). The minimum toxic concentration of olanzapine is given as 0.1 µg/ml (3). Based on these studies, the PM concentration of olanzapine in the present case exceeded therapeutic levels (1). The PM concentration of levomepromazine was around the “normal” PM concentration.

Since both 7-aminoflunitrazepam and 7-aminonitrazepam are pharmacologically inactive metabolites (3), they can be used as markers of ingestion for each parent drug (8). However, the detection of these metabolites does not always indicate that these drugs have been taken just before death. In the present case, flunitrazepam and nitrazepam, the parent drugs of 7-aminoflunitrazepam and 7-aminonitrazepam, respectively, were not detected at all. I am afraid that speculating which drug was consumed based solely on the metabolites detected could result in misinterpretation.

We are familiar with the concept of postmortem redistribution (PMR). As you mentioned, PMR does not occur with nitrobenzodiazepines such as nitrazepam, flunitrazepam and their metabolites (9). However, heart/femoral nitrazepam concentration ratios of 1.95-2.16 have been reported (10).

In the present case, a relatively high concentration of olanzapine was observed (1). Olanzapine is metabolized by cytochrome p450 (CYP)1A2 and CYP2D6 (11), and levomepromazine inhibits CYP2D6, CYP1A2 and CYP3A4, in vivo (12). If anything, we may have to consider drug-drug interactions between these two drugs and further investigation may be necessary.

Yours sincerely,

Hiroshi Kinoshita, M.D., Ph.D.

Naoko Tanaka, Ph.D.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University,

Kagawa 761-0793, Japan

Mitsuru Kumihashi, Ph.D.

Forensic Science Laboratory, Kagawa Prefectural Police Headquarters,

Kagawa 760-8579, Japan

Asuka Ito, M.D., Ph.D.

Ken Nagata, M.D.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University,

Kagawa 761-0793, Japan.

Kunihiko Tsutsui, M.D., Ph.D.

Health Sciences, Faculty of Medicine, Kagawa University,

Kagawa 761-0793, Japan

Shoji Kimura, M.D., Ph.D.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University,

Kagawa 761-0793, Japan