Elsevier

Forensic Science International

Volume 278, September 2017, Pages 177-183
Forensic Science International

Zopiclone concentrations in oral fluid and blood after, administration of therapeutic doses of zopiclone

https://doi.org/10.1016/j.forsciint.2017.07.004Get rights and content

Highlights

  • Oral fluid zopiclone concentration is unsuitable to estimate blood concentration.

  • Intake of a meal reduces the oral fluid to blood concentration ratio.

  • Intake of 10 mg zopiclone can be detected in oral fluid up to 14 days.

Abstract

Purpose

Little is known about the relationship between concentrations in oral fluid (OF) and blood for the widely prescribed hypnotic drug zopiclone. The purpose of this study was to investigate the usefulness of OF zopiclone concentrations to predict blood zopiclone concentrations in order to introduce OF testing as an alternative to more cumbersome blood testing.

Methods

16 healthy young male volunteers received capsules of either 5 or 10 mg zopiclone on two different study days separated by at least one week. Blood and OF were collected simultaneously at baseline and 9 times after intake of zopiclone on each study day. In addition an OF sample was collected 24–81 h after intake. Lunch was served between samples taken 2.5 and 3.5 h after intake. All samples were analysed for zopiclone, and the cut-off was 10 ng/ml in blood and 0.2 ng/ml in OF–buffer mixture.

Results

Zopiclone was detected in all OF samples during the study day. After 24–81 h, all subjects were also positive for zopiclone in OF, except from three subjects ingesting the 5 mg dose. In a single case zopiclone was detected in a baseline OF sample 14 days after intake on an earlier study day. Zopiclone was detected in both OF and blood in 231 OF/blood pairs, and a significant but weak correlation between OF and blood concentration was seen (R2 of 0.30). The median (range) zopiclone OF/blood concentration ratio (ZOBCR) for all samples were 3.3 (0.8–18). The ZOBCR decreased when the OF volume increased. After 30 of 31 given doses of zopiclone, the ZOBCR was higher in samples collected before lunch than samples collected after lunch.

Discussion

Vast intra- and interindividual differences in ZOBCR were found, and the correlation between OF and blood concentration was less pronounced than reported in former studies. In accordance with earlier studies we found a negative correlation between ZOBCR and OF volume. The ZOBCR decreases in relation to recent intake of a meal, probably because stimulated saliva production causes “dilution” of saliva. OF zopiclone concentration appeared unsuitable for estimation of blood zopiclone concentration. Due to long detection time, analysis of zopiclone in OF might be useful to detect non-recent, previous intake.

Introduction

The magnitude of cognitive and psychomotor (side) effects of many drugs are often related to the blood drug concentration [1]. This is reflected in a correlation between the degree of driving impairment and the level of the particular drug in blood [2]. Blood sampling with determination of drug concentration is therefore considered important in the handling of suspected driving under the influence (DUI) cases. However, collection of blood samples would require suitable environment, sterile equipment and trained personnel. Of alternative matrices oral fluid (OF) has several advantages such as easy sample collection which can be performed roadside by most people. Compared to urine OF has reduced adulteration potential and often indicates recent drug intake [3], [4], [5], [6], [7]. In the DRUID project OF screening devices were used to indicate drug use in driving populations [8]. OF is also used widely roadside as a routine matrix in law enforcement of suspected impaired driving, and positive confirmation analysis of drugs in OF may be followed by judicial punishment e.g. in Queensland, Australia [9], [10] and Belgium [11].

The application of the use of OF to determine the magnitude of impairment would require a rather strong and constant correlation between drug concentrations in OF and blood. The measurement of drugs in saliva/OF is also of interest for purpose of therapeutic drug monitoring for some therapeutic drugs [12].

For several potential drugs of abuse it has been attempted to establish conversion factors for drug concentrations in OF to concentrations in whole blood e.g. for amphetamines, opioids, cocaine and benzodiazepines [2], [13]. Cross sectional population studies have found variable ratios between drug concentrations in OF and blood for some drugs, including benzodiazepines [2], [14], [15]. In a controlled experimental study a variable correlation between OF and blood concentrations of oxazepam was demonstrated [16].

Zopiclone is a benzodiazepine-like hypnotic drug widely prescribed in many countries [17], [18]. In previous studies we have found a high prevalence of zopiclone use among Norwegian car drivers [8], [19] and an increased risk of being involved in a car accident among those being prescribed this medication [20]. It has further been demonstrated that blood zopiclone concentrations are related to the degree of impairment as measured by psychomotor and cognitive tests [21], [22]. Little is, however, known about the relationship between concentrations in OF and concentrations in blood (serum) [15], [23].

In the present study we investigated the usefulness of OF zopiclone concentrations to predict blood zopiclone concentrations in order to possibly introduce OF testing as an alternative to more cumbersome blood testing. We performed a controlled experiment on 16 volunteers who were given zopiclone in randomized order in two different doses, at two occasions, followed by repeated measurements of zopiclone concentration in OF and blood during a period of at least ten hours subsequent to drug administration.

Section snippets

Study procedure

16 healthy young males were enrolled in a double blind, placebo-controlled randomized trial. The individuals were given alcohol, placebo or two different doses of zopiclone on four separate study days. The individuals had to fulfil certain inclusion criteria, such as age 20–30, body weight within 70–85 kg and approval of written informed consent. Individuals with a history or presence of mental or significant somatic disease, drug/alcohol abuse, any regular (daily) intake of any prescribed drug

Results

The study population was male college students within the age 20–28 (median 23.5) with a body weight of 70–85 (median 76.5) kg. The time–concentration profiles for all individuals after intake of 5 and 10 mg zopiclone in blood are shown in Fig. 1a and b. After intake of 5 and 10 mg zopiclone the maximum blood drug concentration was reached from 0.5 to 2.5 h after drug intake, with a median Tmax of 1.5 h for both doses. For the blood sample taken 10 h after intake of 5 or 10 mg zopiclone, 1 out of 15

Discussion

In this study we compared the concentrations of zopiclone in OF and blood in samples collected simultaneously, repeatedly over a time period as long as zopiclone could be detected in blood after a single intake. There was some correlation between the concentration in OF and in blood, although vast intra- and interindividual differences in ZOBCR were found. These differences could partly be due to differences in OF sample volume as we found a significant negative correlation between ZOBCR and

Acknowledgements

We are grateful to the Research Unit at the Department of Clinical Pharmacology at Oslo University Hospital, Rikshospitalet, for generously allowing us to use their locations, and to the certified registered nurse anesthetists, Anne Marie Halstensen and Kristin Villa, for their professional assistance. We thank all our colleagues at the Department of Forensic Sciences who have registered, analysed, and stored all the samples in this study, and whose analytical competence has been essential. A

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